A Randomized Phase II Study of Azacitidine Combined with Lenalidomide or with Vorinostat Vs. Azacitidine Monotherapy in Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML): North American Intergroup Study SWOG S1117

Abstract Background: Higher-risk MDS and CMML comprise a spectrum of disorders associated with cytopenias, high risk of transformation to acute myeloid leukemia (AML), and truncated survival. Initial treatment with a hypomethylating agent such as azacitidine (AZA) is considered standard of care. Whether addition of the histone deacetylase inhibitor vorinostat (VOR), which acts synergistically with AZA to reactivate epigenetically silenced genes, or addition of lenalidomide (LEN), which impacts the bone marrow microenvironment, improves response rates compared to AZA monotherapy is unknown. Methods: This Phase II study (ClinTrials.gov # NCT01522976) randomized higher-risk MDS (International Prognostic Scoring System (IPSS) Int-2 or High and/or bone marrow blasts >5%) and CMML patients (pts) with <20% blasts to receive AZA (75 mg/m2/d on d1-7 of a 28d cycle), AZA + LEN (10 mg/d on d1-21), or AZA + VOR (300 mg BID on d3-9). Eligibility criteria included: >18 years (yrs), no previous allogeneic transplant, no prior treatment with any of the study drugs, and adequate organ function; therapy-related (t)MDS was allowed. Pts continued treatment until disease progression, relapse, unacceptable toxicity, or lack of response. Dose reductions occurred for unresolved grade >3 adverse events (per NCI CTCAE) or delayed count recovery. The primary endpoint was improvement in overall response rate (ORR), by intention to treat and reviewed centrally, of one of the combination arms vs. AZA monotherapy per 2006 International Working Group MDS response criteria (complete response (CR) + partial response (PR) + hematologic improvement (HI)). Relapse-free survival (RFS) was from time of response. The study had 81% power to detect a 20% improvement in ORR from 35% to 55%. Results: Of 282 pts enrolled from 3/12–6/14, 276 are included in analyses (6 ineligible pts excluded): 92 on the AZA arm, 93 on AZA+LEN, and 91 on AZA+VOR. Baseline characteristics were well-balanced across arms (Table). Pts received a median of 23 weeks of therapy: 25 of AZA; 24 of AZA+LEN; and 20 of AZA+VOR and were followed for a median of 9 months (range: 0-26). Numbers of pts with notable adverse events >grade 3 for AZA:AZA+LEN:AZA+VOR included febrile neutropenia (10:13:13); gastrointestinal disorders (4:11:23); infections (2:3:3); and rash (2:12:1). Responses were assessable in 260 pts (94%). ORR for the entire cohort was 33%: 19% CR, 1% PR, and 13% HI, with a median RFS of 7 months. ORR was similar across study arms: 36% for AZA, 37% for AZA+LEN (p=1.0 vs. AZA), and 22% for AZA+VOR (p=.07 vs. AZA). CR/PR/HI rates across arms were also similar: 23%/0%/13% for AZA; 18%/1%/17% for AZA+LEN (CR p=.47 vs. AZA); and 14%/1%/7% for AZA+VOR (CR p=.18 vs. AZA); rates of bone marrow exams to assess response were 76%, 67%, and 73%, respectively. HI-P/HI-E/HI-N rates were 21%/15%/5% for AZA, 26%/14%/15% for AZA+LEN, and 12%/8%/4% for AZA+VOR. HI-N rates were higher in AZA+LEN vs. AZA (p=.05) but otherwise were similar across arms. Median time to best response across arms was 15 weeks in AZA, 16 weeks in AZA+LEN, and 16 weeks in AZA+VOR. ORR did not vary significantly across arms in subgroup analyses for tMDS, baseline red blood cell (RBC) transfusion dependence, and by IPSS risk group. ORR for CMML pts for AZA:AZA+LEN:AZA+VOR was 33%:53%(p=.15 vs. AZA):12%(p=.41 vs. AZA). Allogeneic transplantation rates were: 7 pts on AZA, 6 on AZA+LEN, and 9 on AZA+VOR. For AZA:AZA+LEN:AZA+VOR, median RFS was: 6:8:11 months (log-rank p=.3 for combination arms vs. AZA, Figure); and for pts on therapy >6 months, it was 7:7.5:13 months (log-rank p=.11 for AZA+VOR, .74 for AZA+LEN vs. AZA). Conclusions: In higher-risk MDS pts, ORR was similar for AZA monotherapy compared to AZA-containing combination arms, though some subgroups may have benefitted from combination therapy. Differences in types of response may have resulted from differential rates of follow-up bone marrow assessments. While a non-significant signal of a DFS advantage for combination therapy was observed, longer-term outcome data are being assessed. Table Table. Figure Figure. Disclosures Sekeres: Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Off Label Use: lenalidomide, vorinostat for higher-risk MDS. List:Celgene Corporation: Consultancy. Gore:Celgene: Consultancy, Research Funding. Attar:Celgene: Consultancy. Erba:Seattle Genetics: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda Pharmaceuticals International Co.: Research Funding; Astellas Pharma: Research Funding; Celgene: Honoraria, Speakers Bureau.

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Pracinostat in Combination with Azacitidine Produces a High Rate and Rapid Onset of Disease Remission in Patients with Previously Untreated Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood.v124.21.947.947 ◽

2014 ◽

Vol 124 (21) ◽

pp. 947-947 ◽

Cited By ~ 1

Author(s):

Guillermo Garcia-Manero ◽

Ehab Atallah ◽

Olatoyosi Odenike ◽

Bruno C Medeiros ◽

Jorge E. Cortes ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Adverse Events ◽

Board Of Directors ◽

Null Hypothesis ◽

Research Funding ◽

Progressive Disease ◽

De Novo ◽

Phase Ii Study ◽

Advisory Committees

Abstract Background: Pracinostat is a potent oral inhibitor of histone deacetylases (HDAC’s), selective for class I, II and IV isoforms. In-vitro cytotoxicity assays in AML cell lines revealed an IC50 of <0.1µM, and the combination with azacitidine was synergistic (CI=0.44). A Phase I study of single agent pracinostat showed activity in AML and a pilot Phase II study of pracinostat in combination with azacitidine in higher risk MDS demonstrated a complete response (CR)/CR with incomplete blood count recovery (CRi) rate of 89% (Proc ASH:3821, 2012). We report initial results from a Phase II study of pracinostat with azacitidine in previously untreated, elderly AML. Methods: Eligibility includes previously untreated AML (≥ 20% bone marrow blasts), age ≥65 years, deemed inappropriate for intensive induction therapy, with intermediate or high risk cytogenetics based on SWOG criteria. De-novo, treatment-related, or AML evolved from an antecedent hematologic disorder (AHD) are allowed. Pracinostat is administered orally (60 mg) 3 days a week (e.g., Monday, Wednesday, Friday) for 3 weeks followed by a 1 week break. Azacitidine is administered subcutaneously or intravenously (75 mg/m2) day 1-7 or day 1-5 and 8-9 of each 28-day cycle. The primary endpoint is CR+CRi+ morphologic leukemia free state (MLFS) according to IWG criteria. Response assessments occur at the end of cycle 1 or 2 followed by every other cycle or when clinically indicated. A Simon 2-stage statistical design is utilized with the following assumptions: null=0.10, alternate=0.25, α=0.10, power=0.90. Transition from stage 1 to 2 requires ≥ 3/27 response events; the null hypothesis will be rejected if ≥ 7 response events are observed in the total planned sample of 40 patients. Results: As of August 01, 2014, 21 patients have been enrolled from 12 study sites and are evaluable for safety; 14 are evaluable for efficacy (Table 1), and 7 are ‘too early’ for response assessment. Baseline disease characteristics include: median age 77 (range 69-84); 16 de novo AML, 4 evolved from AHD, 1 treatment related; 11 intermediate-risk, 8 high-risk cytogenetics, and 2 are pending; baseline bone marrow blast counts ranged from 22% to 89%. The primary endpoint of CR +CRi+MLFS was observed in 8 of 14 evaluable patients (57%), the majority after 1 or 2 cycles. No responders have progressed. The most common treatment emergent adverse events (TEAE) were neutropenia/neutropenic fever (n=15), thrombocytopenia (n=12), nausea (n=10), fatigue (n=8), and anemia (n=7). Serious adverse events include febrile neutropenia (n=6) and pulmonary infiltrate/pneumonia (n=2). Three patients discontinued study therapy due to a TEAE, including one each with cellulitis, bacteremia, and subdural hematoma after a fall. There have been 3 deaths on study: 1 bacteremia, 1 subdural hematoma, and 1 progressive disease. Abstract 947. Table 1 Patient Number Days on Study Baseline BM Blast % 1st On-Study BM Blast % Subsequent On-Study BM Blast % Best Response on Study 2 172+ 22 1 (C2) --- CR 3 165+ 24 4 (C1) 0 (C4) CRi 5 162+ 27 9 (C1) 1 (C4) CRi 6 156+ 81 9 (C1) 0 (C4) CRi 7 148+ 78 44 (C1) 17 (C3), 0 (C5) CR 8 114+ 89 4 (C1) --- CR 10 86+ 45 3 (C1) --- CRi 12 81+ 41 2 (C2) --- CRi 4 90 22 43 (C2) Off due to SAE SD 11 56 37 60 (C2) --- PD 15 28 70 --- Patient Withdrew 17 28 60 --- PD 1 26 70 --- Off due to AE 9 26 38 --- Off due to AE +=Patients continue on study; C=cycle; SD=Stable Disease; PD=Progressive Disease Conclusions: The study has achieved the primary goal of rejecting the null hypothesis. The CR+CRi +MLFS response rate estimate of 57% is high compared to historical results with hypomethylating agents alone in this population, and the responses occur rapidly, most within the first 2 cycles. The combination appears tolerable with no unexpected toxicities. Recruitment continues to the final planned sample size of 40 to further define the tolerability and efficacy of the regimen, including remission duration. Updated data will be presented at the meeting. Disclosures Garcia-Manero: MEI Pharma, Inc.: Consultancy. Off Label Use: Azacitidine is not approved for use in acute myelogenous leukemia.. Odenike:Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Algeta Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Suneisis Pharmaceuticals : Honoraria, Membership on an entity's Board of Directors or advisory committees. Medeiros:MEI Pharma, Inc: Research Funding. Cortes:Celgene: Research Funding. Esquibel:MEI Pharma, Inc.: Employment. Cha:MEI Pharma, Inc.: Employment. Khaled:Sequenom: Research Funding.

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Phase II Study of the Combination of Ixazomib with Lenalidomide As Maintenance Therapy Following Autologous Stem Cell Transplant in Patients with Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.3155.3155 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3155-3155 ◽

Cited By ~ 5

Author(s):

Jatin J. Shah ◽

Lei Feng ◽

Donna Weber ◽

Sheeba K Thomas ◽

Michael Wang ◽

...

Keyword(s):

Respiratory Failure ◽

Adverse Events ◽

Maintenance Therapy ◽

Board Of Directors ◽

Dose Reduction ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Study ◽

Advisory Committees ◽

Grade 3

Abstract Background: The role of maintenance lenalidomide (Len) in the post autologous stem cell transplant (ASCT) setting has been based on a significant benefit in progression-free survival (PFS) and time to progression (TTP) in the CALBG 100104 and IFM 2005-02 trials, and overall survival (OS) benefit in the CALBG100104 trial. To date, the use of a proteasome inhibitor (PI) as maintenance therapy has been limited by the inconvenience of its IV/subcutaneous administration. Ixazomib, an oral PI, may provide an alternative maintenance therapy. Here we report the results of a single arm phase II study combining ixazomib and lenalidomide as post ASCT maintenance therapy in patients with newly diagnosed multiple myeloma (NDMM). Methods: This is a single arm phase II study of the combination of lenalidomide/ixazomib (LI) maintenance therapy for NDMM paients post ASCT. The primary objective was to establish safety and efficacy of Len as maintenance therapy. The secondary objectives were to evaluate the incidence of secondary primary malignancies (SPMs), overall response rate (sCR/nCR/VGPR/PR), TTP, time to next therapy, and toxicity profile. Eligible patients had undergone ASCT, with melphalan as a preparative regimen, within 12 months of initiation of induction therapy. Patients were required to start maintenance therapy 60-180 days post ASCT. Treatment consisted of 28 day cycles of ixazomib 4 mg on days 1, 8, 15, and lenalidomide 10 mg daily on days 1-28. Len was increased to 15 mg after 3 months if well tolerated. Based on clinical experience from ongoing phase III studies, the protocol was later amended to reduce the starting dose of ixazomib to 3 mg. Adverse events were graded by NCI-CTCAE v4. Response was assessed by the modified International Uniform Response Criteria. Results: 65 patients (pts) were enrolled with a median age of 60 (range 39-74); 65% (42/65) were male. 39 pts had ISS stage I disease, 13 had Stage II; and 13 had stage III. Of the 65 pts, 47 remain on therapy and as of June 2015, pts have received a median of 10 cycles (range 1-30). The median PFS has not been reached however, the estimated 2-year PFS was 83%. 18 pts are off study: 7 due to progressive disease (PD), 3 at PI discretion, and 8 due to consent withdrawal. 6/7 pts with PD had high risk disease and received 2, 5, 7, 7, 9, 11, and 24 cycles of study therapy. Among the 7 pts with PD, the median PFS post ASCT was 13 months (6-34 months); 3 pts have died with an OS of 15, 27 and 31 months. Grade 3/4 hematologic adverse events (AEs) included: grade 3 (G3) anemia (2), G3 neutropenia (13), G4 neutropenia (2); and G3/4 thrombocytopenia (7). Grade 3/4 drug-related non-hematologic AEs included: G3 elevated aspartate aminotransferase (3); G3 back pain (2); G3 constipation (4); G3 creatinine increase (2); G3 nausea and diarrhea (2); G3 fatigue (4). 10 pts had G1/2 rash and 8 pts had G3 rash. 42 patients had G1/2 peripheral neuropathy (PN); 1 pt had G3 PN; and 2 pts had G3/4 respiratory failure. There were no second primary malignancies. Infectious complications included G3 urinary tract infections (2); G3/4 upper respiratory tract infections (4); G3 sinusitis (1); G3 pneumonia (7); G3 influenza (2); G4 infection (1). Other AEs included G4 renal failure due to progressive disease (1); G3 non cardiac chest pain (1); G3 emesis (1); G4 respiratory failure and G4 sepsis/respiratory failure (2). 10 patients required a dose reduction of ixazomib for PN (5); neutropenia (3); thrombocytopenia (1), and hearing loss (1). 1 pt discontinued ixazomib and remained on Len due to persistent PN. 11 pts had a dose reduction in Len to 10 mg for 21 of a 28 day cycle due to cytopenias (neutropenia or thrombocytopenia); 5 pts had a dose reduction to 5 mg due to rash/pruritus in 4 pts and 1 pt due to neutropenia. Conclusions: Long term administration of combination of lenalidomide/ixazomib as maintenance therapy post ASCT is feasible with pts ongoing at 30+ cycles. The incidence of adverse events was similar to historical experience with lenalidomide alone; hematologic adverse events were manageable with dose reductions. The incidence of PN was limited to grade 1/2 events and 1 grade 3 event with no other unexpected toxicity. The combination is safe, feasible, well tolerated and experience to date supports further exploration in phase III studies. Disclosures Shah: Celgene: Consultancy, Research Funding. Thomas:Celgene: Research Funding; Novartis: Research Funding; Idera Pharmaceuticals: Research Funding. Wang:Celgene: Research Funding. Orlowski:Celgene: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Acetylon: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Millennium Pharmaceuticals: Consultancy, Research Funding; Spectrum Pharmaceuticals: Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Forma Therapeutics: Consultancy; BioTheryX, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

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Carfilzomib Thalidomide and Dexamethasone Is Safe and Effective in the Treatment of Relapsed/Refractory Multiple Myeloma: An Open Label Phase II Australasian Leukaemia and Lymphoma Group (ALLG) MM 018/ Asian Myeloma Network (AMN) 002 Study

Blood ◽

10.1182/blood-2020-139174 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-40

Author(s):

Hang Quach ◽

Simon J Harrison ◽

Je-Jung Lee ◽

Nichloas Murphy ◽

Jae Hoon Lee ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Board Of Directors ◽

Phase Ii ◽

Primary Endpoint ◽

Research Funding ◽

Open Label ◽

Advisory Committees ◽

Open Label Phase ◽

Grade 3

Background: The combination of carfilzomib with immunomodulatory drugs (IMiDs) and dexamethasone is active in multiple myeloma (MM). Carfilzomib, thalidomide, and dexamethasone (KTd) has been studied in upfront MM treatment but has not been studied in the setting of relapsed/refractory myeloma (RRMM). The ALLG MM018/ AMN002 is an open-label phase II study of KTd in patients with RRMM. This study was conducted across 16 sites across Australia, New-Zealand, Singapore, South Korea and Taiwan. Method: Patients with RRMM with 1-3 prior lines of treatment were given carfilzomib [K: 20mg/m2 IV cycle 1 days 1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from cycle 1 day 8 onwards], thalidomide (T: 100mg po nocte) and dexamethasone [dex: 40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, T was omitted, and K was given on days 1,2,15,16 and dex days 1,15 every 28-day cycles for a further six cycles. The primary endpoint was PFS. Secondary endpoints were ORR, overall survival, adverse events, and quality of life (QoL). The study had an 80% power to detect a ≥70% PFS at 6.5 months compared to historical ≤50% PFS at 6.5 months expected with Td (Kropff, M. et al. Haematologica 2012), at a significance level of 0.05. Results: This study has completed accrual. Eighty-three patients [median age of 66 years (42-85)] were enrolled with a median follow up of 15.9 (0.9-26) months. ORR rates were 86.4% (≥VGPR 70.2%). Median PFS was 20m (95% CI 15.9-26m). PFS at 6.5 months was 76.2% (95% CI 73.6-84.9%). Median OS has not been reached, and was 75% at 20 months. The most common grade ≥3/4 AEs were peripheral neuropathy (16%), upper respiratory tract infections (12%), dyspnoea (14%), and hypertension (10%). Grade ≥3/4 cardiac AEs occurred in 6%. The median carfilzomib dose that was delivered was 70.7% (32.8-92.6%) of the target dose. Thus far, 41% of patients have completed the intended 18 cycles of treatment. 21% of patients ceased therapy early. The most common reason for early treatment cessation was disease progression (30%) and adverse events (15%). Fifteen patients (18%) have died, 11 were due to MM, two from infection, one from an ischaemic cardiac event, and one from a traffic accident. QoL, as measured by the EQ-5D-5L instrument, remained stable throughout treatment. Conclusion: The ALLG MM018/AMN 002 study has met its primary endpoint. The KTd schedule as outlined in this study is efficacious in patients with RRMM, resulting in a prolonged PFS and a safety profile in line with previous reports for each of carfilzomib and thalidomide. KTd is an active option in jurisdictions where the cost of other IMiDs prohibits regulatory funding. Comparisons of efficacy and adverse events between the Caucasian and Asian populations will be presented at the meeting. Disclosures Quach: Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Haemalogix: Consultancy. Augustson:Roche: Other: Support of parent study and funding of editorial support. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Soo:Hanmi: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

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Additional Analyses of a Randomized Phase II Study of Azacitidine Combined with Lenalidomide or with Vorinostat Vs. Azacitidine Monotherapy in Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML): North American Intergroup Study SWOG S1117

Blood ◽

10.1182/blood.v126.23.908.908 ◽

2015 ◽

Vol 126 (23) ◽

pp. 908-908 ◽

Cited By ~ 14

Author(s):

Mikkael A. Sekeres ◽

Megan Othus ◽

Alan F. List ◽

Olatoyosi Odenike ◽

Richard M. Stone ◽

...

Keyword(s):

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Study ◽

Response Duration ◽

High Volume ◽

Centers Of Excellence ◽

Advisory Committees ◽

Data Safety ◽

Randomized Phase Ii

Abstract Background: The few therapies available to treat higher-risk MDS and CMML have limited impact on outcome. We previously reported initial results of S1117, which compared overall response rates (ORRs) of azacitidine (AZA) monotherapy to AZA combined with the histone deacetylase inhibitor vorinostat (VOR), or the immunomodulator lenalidomide (LEN)( ASH 2014 LBA-5). We now report updated response data and overall survival (OS), subgroup analyses, impact of cytogenetics, and effect of treatment center volume/centers of excellence on outcome. Methods: This randomized, Phase II study (ClinTrials.gov # NCT01522976) enrolled higher-risk MDS (International Prognostic Scoring System (IPSS) Int-2 or High and/or bone marrow blasts ≥5%) and CMML adult patients (pts) with <20% blasts from 3/12-6/14 to receive AZA (75 mg/m2/d on d1-7 of a 28d cycle), AZA + LEN (10 mg/d on d1-21), or AZA + VOR (300 mg BID on d3-9). Pts continued treatment until treatment failure, defined as disease progression, relapse, significant or unresolved toxicity, or lack of response. Dose reductions occurred for grade ≥3 adverse events (per NCI CTCAE) or delayed count recovery. Cytogenetic risk groups were defined per IPSS-R. The primary endpoint was improvement in ORR, by intention to treat and reviewed centrally, of one of the combination arms vs. AZA per 2006 International Working Group MDS response criteria (complete response (CR) + partial response (PR) + hematologic improvement (HI)). OS was from study entry. MDS Centers of Excellence (MCE) were defined per MDS Foundation; center volume was defined as low (1-4 pts enrolled) or high (5-17 pts). Results: Of 277 pts, 92 received AZA, 93 AZA+LEN, and 92 AZA+VOR. Baseline characteristics, previously reported, were similar across arms. Pts received a median of 22 weeks of therapy and were followed for a median of 10 months (range: 0-30). Non-protocol defined dose modification and protocol discontinuation due to toxicity occurred more frequently in combination arms vs. AZA (p=.0014 and p=.018, respectively). Responses are now assessable in all pts (Table 1). ORR was statistically similar for combination arms vs. AZA, with a trend for longer response duration (p=.083) for combinations. Within HI, AZA+LEN pts had higher HI-n than AZA pts (16% vs. 5%, p=.031). ORR for CMML pts was significantly higher for LEN+AZA vs. AZA (63% vs. 29%, p=.04), with a trend for longer response duration for combinations (p=.06); no differences in ORR were seen for therapy-related MDS, IPSS subgroups, or transfusion-dependent pts. Allogeneic transplantation rates were similar. Median OS (Figure) for AZA:AZA+LEN:AZA+VOR was 15:18 (p=.38):17 (p=.17) months; p=.19 for combination arms vs. AZA. Median OS after failure was 7:9 (p=.6):9 (p=.05) months; p=.15 for combination arms after failure vs. AZA. For pts on therapy >6 months, there was a trend (p=.08) for higher ORR for AZA+LEN vs. AZA, though response duration was similar; median OS was 18:21 (p=.44 vs. AZA):21 months (p=.45 vs. AZA). Cytogenetic risk category distribution and ORR was similar across arms. OS (compared to Very Good/Good) was worse for Poor (HR 2.07, p=.022) and Very poor (HR 4.41, p<.001), without significant modification by treatment arm (Table 2). Compared to pts without identified cytogenetic abnormalities (abn), ORR across arms was better for pts with Chr 5 abn (OR 2.38, p=.004); OS was better for normal (HR .42, p<.001) and worse for Chr 5 abn (HR 3.1, p<.001), -7 (HR 2.69, p<.001), and 17p (HR 2.61, p<.001). While small numbers prevented definitive conclusions for treatment arm effect, combinations trended towards improving OS in Normal and Chr 5 abn only. The outcome of all pts and pts on discrete study arms treated at MCE (n=75) or high volume (n=138) sites were similar to non-MCE or low-volume sites for ORR, non-protocol defined dose modifications, dose adjustment in first 4 cycles, time to off-protocol (HR 1.2, p=.21 and HR .94, p=.64), and OS (HR .81, p=.3 and HR .77, p=.12). Conclusions: In higher-risk MDS pts, ORR and OS was similar for AZA monotherapy compared to combination arms, while for CMML pts, ORR was significantly higher with AZA+LEN. For cytogenetic subgroups, OS was worse for Chr 5 abn, -7, and 17p, and may be improved by combinations in normal or Chr 5 abn. MCE or treatment at a high volume site did not impact these effects or outcomes. Figure 1. Responses Figure 1. Responses Figure 2. Cytogenetics Figure 2. Cytogenetics Figure 3. Figure 3. Disclosures Sekeres: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. List:Celgene Corporation: Honoraria, Research Funding. Odenike:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stone:Merck: Consultancy; Celgene: Consultancy. Gore:Celgene: Consultancy, Honoraria, Research Funding. Buckstein:Celgene: Honoraria, Research Funding. Fang:Affymetrix: Research Funding. Attar:Agios Pharmaceuticals: Employment. Erba:Ariad: Consultancy; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Jannsen (J&J): Other: Data Safety and Monitoring Committees ; Ariad: Consultancy; Celgene: Consultancy, Speakers Bureau; GlycoMimetics: Other: Data Safety and Monitoring Committees; Seattle Genetics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Millennium/Takeda: Research Funding; Celator: Research Funding; Celator: Research Funding; Astellas: Research Funding; Astellas: Research Funding; Sunesis: Consultancy; Daiichi Sankyo: Consultancy; GlycoMimetics: Other: Data Safety and Monitoring Committees; Jannsen (J&J): Other: Data Safety and Monitoring Committees.

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A Phase-Ib/II Study of Ruxolitinib Plus Pomalidomide in Myelofibrosis

Blood ◽

10.1182/blood.v126.23.826.826 ◽

2015 ◽

Vol 126 (23) ◽

pp. 826-826 ◽

Cited By ~ 7

Author(s):

Frank Stegelmann ◽

Markus Bangerter ◽

Florian H Heidel ◽

Martin Griesshammer ◽

Holger Hebart ◽

...

Keyword(s):

Combination Therapy ◽

Board Of Directors ◽

Clinical Improvement ◽

Research Funding ◽

Severe Neutropenia ◽

International Prognostic Scoring System ◽

Advisory Committees ◽

Phase Ib ◽

Treatment Interruptions ◽

Rbc Transfusion

Abstract Background: Myelofibrosis (MF) patients (pts) frequently suffer from constitutional symptoms, splenomegaly, and cytopenia. While ruxolitinib (RUX) is available for the treatment of symptomatic splenomegaly and constitutional symptoms in MF, therapeutic options for the treatment of cytopenia are limited. Recent data indicate that the immunomodulatory drug pomalidomide (POM) may improve anemia and thrombocytopenia in a subset of MF pts (e.g. Tefferi et al., J Clin Oncol 2009). We designed a single arm, multicenter phase-Ib/II combination study of RUX and POM (MPNSG-0212 trial, NCT01644110) to evaluate potential synergistic effects of both drugs in MF. Study Design: Primary endpoints are response rate after 12 treatment cycles (28 days each) according to IWG-MRT criteria (Tefferi et al., Blood 2006) and achievement of red blood cell (RBC) transfusion independence (Gale et al., Leuk Res 2011). Secondary endpoints are safety, quality of life, progression-free survival, and overall survival. Main inclusion criterion is pre-treated or untreated primary or secondary (post-ET / post-PV) MF with anemia (Hb <10 g/dL and/or RBC transfusion dependency). Key exclusion criteria are suitability for allotransplant, low platelet count (<100 /nL), and severe neutropenia (ANC <0.5 /nL). While POM is given at the fixed dosage of 0.5 mg QD, RUX is started at 10 mg BID with dose modifications being allowed to optimize efficacy and to manage myelosuppression. According to a Simon´s two-stage design, recruitment will be extended to a total number of 72 pts if response is achieved in a minimum of 12/37 pts tested initially. Results: Safety of the combination therapy was evaluated favorably by an independent safety monitoring committee after treatment of the first 6 pts as reported previously (Stegelmann et al, ASH 2014). Here, we present follow-up data from 25 pts. Median age of the study population was 75 years (range 51-82). Ten of 25 pts (40%) had one or more previous therapies. The most frequent previous drugs were hydroxyurea (n=6), ruxolitinib (n=3), EPO (n=2), pomalidomide (n=2), and steroids (n=2). Median Hb at study entry was 8.6 g/dL (range 6.8-10.6); 6 pts (24%) were RBC transfusion dependent. Median spleen size measured by ultrasound was 18 cm (range 13-28). Eight pts (32%) were intermediate-1, 10 pts (40%) intermediate-2, and 7 pts (28%) high-risk according to the dynamic international prognostic scoring system (DIPSS). Mutation frequencies of JAK2 V617F, MPL W515L, and CALR exon 9 were 72%, 12%, and 16%, respectively. ASXL1 was mutated in 5 pts (20%). Regarding safety, 287 adverse events (AE) of any grade (CTCAE 1-5) were recorded. Among these, worsening of anemia (°3/°4) was the most frequent AE (n=35 in 9 pts), followed by musculoskeletal pain (n=25 in 6 pts; °1-°3), and constitutional symptoms (n=13 in 2 pts; °1-°3). In total, 11 serious AE (SAE) CTCAE °2-5 were recorded. While 9 SAE (pneumonia °3, n=3; cardiac decompensation °5, malignant melanoma °2, septic shock °5, syncope °3, and TIA °2, worsening of general condition °3, n=1 each) were considered non-related to the study drugs, 2 SAE (hemoglobin °4, neuropathy °3) were considered related. Of note, neuropathy resolved after end of study. Treatment interruptions and dose reductions of RUX were uncommon. RUX could be step-wise increased to 15 or 20 mg BID in 10 pts (40%). Median time on treatment was 8 28-days cycles (range 1-13) in 24 pts, while one patient has not yet started therapy; 14 pts (56%) are still on study treatment. A total of 10 pts (40%) discontinued, due to death (n=2), no response after 12 cycles (n=5), or withdrawal of informed consent (n=3). Within this short observation time, 3 pts experienced ´clinical improvement´ (CI) according to IWG-MRT criteria in the following categories: i) spleen reduction, ii) spleen reduction + increase of Hb, and iii) increase of both Hb and ANC. RBC transfusion independency criteria have not yet been fulfilled in transfusion dependent pts. None of the study pts progressed during treatment. Conclusions: Taking into account that the majority of study pts were pre-treated and at advanced risk, the combination therapy of RUX and POM was well tolerated and is feasible. First efficacy evaluation shows that clinical improvement regarding reduction of splenomegaly and improvement of cytopenia is achieved in a subset of MF pts. Recruitment of the study continues. An update on safety and efficacy will be presented at the meeting. Disclosures Hochhaus: ARIAD: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Scheid:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Schlenk:Arog: Honoraria, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Teva: Honoraria, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees.

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Bortezomib-Pomalidomide-Dexamethasone (VPD) As Novel Induction Therapy in Newly-Diagnosed Multiple Myeloma: Early Safety Data from an Ongoing Single Arm Phase-II Investigator-Initiated Clinical Trial (PRIME Study)

Blood ◽

10.1182/blood-2021-151718 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2752-2752

Author(s):

Vivek S Radhakrishnan ◽

Naveed Tamboli ◽

Shreya Das ◽

Jeevan Kumar Garg ◽

Arijit Nag ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Safety Data ◽

Bone Lesions ◽

Newly Diagnosed ◽

Advisory Committees ◽

Tertiary Center

Abstract Introduction: Pomalidomide is a third-generation immunomodulatory drug approved for relapsed and/or refractory Multiple Myeloma (RRMM). In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib, and dexamethasone demonstrated superior efficacy in patients with RRMM. PRIME study (CTRI/2019/10/021618) is testing this combination in Newly Diagnosed Multiple Myeloma (NDMM) Aim: To determine safety of Pomalidomide in combination with Bortezomib and dexamethasone (VPD) in NDMM Study design: A prospective, single arm, phase II study from a tertiary center. Both transplant eligible and ineligible patients with NDMM aged between 18-70 years are being recruited in the study. Patients with Plasma cell leukemia, POEMS and amyloidosis were excluded. The regimen consists of weekly Bortezomib 1.3mg/sq.m (subcutaneous), Tab. Pomalidomide 2-4mg once daily for 21days, and Tab Dexamethasone 20mg twice weekly, with the cycle repeating every 28 days, 9-12 cycles. Here we report the adverse events (AE) by NCI CTCAE v5.0, upon recruiting 26 patients, as predetermined in the study. Results: Of the proposed 45-50 patients, 26 patients were enrolled in the study between April 2020 to May 2021 and 23 (88.4%) have completed 4 cycles of VPD. The median age is 55years (18-70), and gender ratio 1:1. At disease presentation, bone lesions were the commonest (96.2%, n=25), IMWG high risk cytogenetics were seen in 42.4% (n=11), RISS-2 in 69.3% (n=18), IgG kappa paraproteinemia in 54% (n=14) patients and ECOG performance score 2-3 in 57.6%(n=15). Ten (38.5%) patients have completed 9 cycles, and 3 underwent auto-transplant (between Cycle 4 & 6). Protocol adherence was 96.1% (25/26 patients). Table-1 shows drug-induced toxicity, hematological toxicities were the commonest. Two patients withdrew consent in view of bortezomib-induced peripheral neuropathy. Serious adverse events (SAE) were reported in 9 (34.6%) patients and were considered unrelated to the regimen by the safety committee (PSVT=1, Bony pain=2, dyspnea=1, pneumonia=1, constipation=1, diarrhea=1, hypotension=1) and one death due to SARS-CoV2 pneumonia. Treatment delays of 2 weeks in 4 patients (SARS-CoV2 = 3, Syncope = 1) After 4 cycles (n=23), 6 (26%) patients were in stringent Complete Response (sCR), 17(74%) in Very Good partial response (VGPR) and 13 (56.5%) are Measurable Residual Disease (MRD) negative. Of 10 patients who completed cycle 9, 9 were MRD negative and 1 showed disease progression. Conclusion: Safety data from the PRIME study demonstrates that VPD regimen has a favorable tolerance profile in patients with NDMM. Early efficacy signals are encouraging, and recruitment continues. Figure 1 Figure 1. Disclosures Radhakrishnan: Dr Reddy's Laboratories: Honoraria, Membership on an entity's Board of Directors or advisory committees; Emcure Pharmaceuticals: Research Funding; Intas Pharmaceuticals: Research Funding; Janssen India: Honoraria; NATCO Pharmaceuticals: Research Funding; Novartis India: Membership on an entity's Board of Directors or advisory committees; Roche India: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca India: Honoraria, Speakers Bureau; Bristol-Myers-Squibb India: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cipla Pharmaceuticals India: Research Funding; Aurigene: Speakers Bureau. Garg: Dr Reddys Laboratories: Honoraria, Speakers Bureau. Nair: Dr Reddy's Laboratories: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Intas pharmaceuticals: Honoraria, Speakers Bureau; Mylan pharmaceuticals: Honoraria; Novartis India: Honoraria; Fresenius Kabi India: Honoraria; Cipla Pharmaceuticals: Honoraria, Speakers Bureau; Janssen India: Honoraria, Speakers Bureau. Chandy: Janssen: Honoraria; Pfizer: Honoraria; Intas Pharmaceuticals: Research Funding.

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Preliminary Results from a Phase II Study of the Combination of Azacitidine and Pembrolizumab in Patients with Higher-Risk Myelodysplastic Syndrome

Blood ◽

10.1182/blood-2018-99-115720 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 464-464 ◽

Cited By ~ 3

Author(s):

Kelly S. Chien ◽

Jorge E. Cortes ◽

Gautam Borthakur ◽

Courtney D. DiNardo ◽

Naval G. Daver ◽

...

Keyword(s):

Clinical Trial ◽

Myelodysplastic Syndrome ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

International Prognostic Scoring System ◽

Advisory Committees ◽

Genetics Research ◽

Ongoing Phase

Abstract Background: The survival of patients with myelodysplastic syndrome (MDS) after hypomethylating agent (HMA) failure is poor at about 4 to 6 months. The exposure of CD34 positive cells from patients with MDS to HMA has been shown to result in increased expression of PD-1 and PD-L1, with a sequential increase in the expression of PD-1 and PD-L1 particularly in patients that have failed HMA (Yang H, Leukemia 2014). Pembrolizumab is a humanized monoclonal antibody targeting PD-1, thus blocking its interaction with ligands PD-L1 and PD-L2, that has been FDA-approved for certain solid tumors. Consequently, we designed an ongoing phase II clinical trial to evaluate the safety and clinical activity of the combination of azacitidine and pembrolizumab in patients with higher-risk MDS. Methods: Adult patients with intermediate-1 or higher disease by the International Prognostic Scoring System (IPSS) were eligible for the study. Patients were divided into two cohorts: those who had not received prior therapy and those who had not responded to, progressed on, or relapsed after HMA therapy, with a goal enrollment of 20 patients per cohort. Patients received azacitidine 75 mg/m2 IV or SQ daily for 7 days on a 28-day cycle and pembrolizumab 200 mg IV starting on cycle 1 day 1 and every 3 weeks thereafter independent of azacitidine dosing schedule. The endpoints were overall response rate and safety. Patients were discontinued from the clinical trial if there was disease progression, unacceptable adverse experiences, intercurrent illness preventing further administration of study treatment, confirmed positive serum pregnancy test, noncompliance, loss to follow-up, completion of 24 months of uninterrupted treatment with pembrolizumab or 35 administrations of the study medication (whichever occurred later), lack of efficacy, or any other reason leading to the investigator's decision for withdrawal. Clinical trial information: NCT03094637. Results: At data cut-off (July 2018), 18 patients have been treated with azacitidine and pembrolizumab with a median follow-up time of 16 weeks and 9 patients continuing on treatment in cycles 1-6. Twelve patients were enrolled in the HMA failure cohort and 6 patients in the previously untreated MDS cohort. Of the 12 patients evaluable for response, 7 were in the HMA failure cohort and 5 in the previously untreated MDS cohort. In the HMA failure cohort, 1 patient achieved CR, 1 patient demonstrated hematological improvement with mCR or CRi, and 5 patients progressed. In the previously untreated MDS cohort, 1 patient attained CR, 2 patients exhibited hematological improvement, 1 patient showed progression, and 1 patient died due to treatment-unrelated causes. The most frequently observed mutations in the 5 responding patients were TET2 in 3 patients and ASXL1, DNMT3A, and RUNX1 in 2 patients each. Three of the responders had diploid cytogenetics, 1 had del(10), and 1 had complex karyotype. Treatment was overall well-tolerated. Most common treatment-related adverse events (all grades) were neutropenia (22%); elevated ALT, elevated AST, anemia, and injection site reactions (17%); and constipation, joint pain, anorexia, pneumonitis, and pneumonia (11%). Conclusions: In this ongoing phase II trial, preliminary data suggest that azacitidine and pembrolizumab was relatively safe and may have antitumor activity in patients who failed HMA. Disclosures Cortes: Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding. DiNardo:Karyopharm: Honoraria; Medimmune: Honoraria; Agios: Consultancy; Bayer: Honoraria; Celgene: Honoraria; Abbvie: Honoraria. Daver:Sunesis: Research Funding; ARIAD: Research Funding; BMS: Research Funding; Karyopharm: Research Funding; Incyte: Consultancy; Pfizer: Consultancy; Sunesis: Consultancy; Otsuka: Consultancy; Kiromic: Research Funding; Daiichi-Sankyo: Research Funding; Karyopharm: Consultancy; Novartis: Consultancy; Incyte: Research Funding; Alexion: Consultancy; Novartis: Research Funding; ImmunoGen: Consultancy; Pfizer: Research Funding. Jain:Adaptive Biotechnologioes: Research Funding; Pfizer: Research Funding; Astra Zeneca: Research Funding; Genentech: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Celgene: Research Funding; BMS: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Incyte: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Pharmacyclics: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Cellectis: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Infinity: Research Funding; Seattle Genetics: Research Funding; ADC Therapeutics: Research Funding; Verastem: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Safety and Efficacy of Combined Ruxolitinib and Thalidomide in Patients with Myelofibrosis: Initial Results of a Phase II Study

Blood ◽

10.1182/blood-2018-99-114125 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 354-354 ◽

Cited By ~ 7

Author(s):

Raajit K. Rampal ◽

Srdan Verstovsek ◽

Sean M Devlin ◽

Eytan M. Stein ◽

Tapan M. Kadia ◽

...

Keyword(s):

Platelet Count ◽

Combination Therapy ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Single Agent ◽

Response Assessment ◽

Platelet Response ◽

Advisory Committees ◽

Grade 3

Abstract Background: Among the most frequent and challenging hematologic manifestations of myelofibrosis (MF) are anemia and thrombocytopenia, the presence of which portends an adverse outcome. Few effective modalities to address these cytopenias exist, particularly thrombocytopenia. Further, although the FDA-approved JAK1/2 inhibitor Ruxolitinib (RUX) has demonstrated significant clinical efficacy in MF patients, RUX frequently results in anemia and thrombocytopenia. Thrombocytopenia in particular often results in dose attenuation of RUX. Thalidomide (THAL) is a first-in-class immunomodulatory agent. Studies of THAL in MF patients, alone and with prednisone, have demonstrated improvements in anemia and thrombocytopenia. We therefore sought to examine whether combination of RUX and THAL could result in improvement in both disease-related and therapy-related cytopenias, as well as improve overall disease response in patients with MF. Here we report initial analysis of this study (NCT03069326). Methods: We conducted a multicenter two stage phase II trial designed to assess the effect of RUX and THAL combination in subjects with primary, post-polycythemia vera, or post-essential thrombocythemia myelofibrosis. Patients taking RUX at the time of enrollment must have had less than PR per IWG-MRT/ELN 2013 criteria, or be refractory, to RUX single-agent therapy. Patients must have been taking RUX for a minimum of 3 months, and must have been on a stable dose of RUX for a minimum of 4 weeks immediately prior to enrollment. Treatment-naïve patients received single-agent RUX for 3 months (run-in phase) per label, and went on to combination therapy if they achieved less then a PR per IWG-MRT/ELN criteria. Each cycle of therapy was 28 days. Response assessment was evaluated according to the IWG-MRT/ELN 2013 criteria. Platelet response criteria in patients with baseline thrombocytopenia (less than lower limit of normal) included: Major response (≥75% increase in platelet count), Intermediate Response (≥50% increase) and Minor Response (≥25% increase). Adverse events were assessed using the NCI CTCAE v. 4.0. The primary endpoint was the proportion of treated subjects that achieved a response by IWG-MRT criteria and by platelet response criteria. Results: A total of 25 patients are planned to be accrued. At the time of this writing, a total of 18 patients have been accrued. The median age was 70.5 years (47-85). 8 patients had received prior therapies other than RUX, including imetelstat, momelotinib, danazol, pomalidomide, darbepoetin alpha and sotatercept. 7 patients enrolled to the run-in phase. 14 patients received red blood cell transfusions prior to study enrollment. Evaluation of platelet count in patients with baseline thrombocytopenia demonstrated a significant increase in platelet count at cycle 3 of therapy compared to baseline (Figure 1A and B; P<0.05). An increase in Hgb was observed over successive cycles of combination therapy (Figure 1C and D). 5 of 18 accrued patients completed ≥6 cycles of combined therapy at the time of abstract submission and were thus evaluable for response assessment. The overall response rate in these patients was 80% (4/5 patients). Clinical Improvement (Anemia response and Symptom response) occurred in 3 patients (both responses observed in all 3 patients). Major platelet response was observed in 4 of 5 patients with baseline thrombocytopenia. 1 patient met criteria for spleen response (Table 1). Grade 3/4 non-hematologic adverse events regardless of attribution included; limb edema, diverticulitis, hypertension, syncope. 1 patient experienced a thromboembolic event. 1 patient experienced a grade 3 hematologic AE (neutropenia). Conclusions: The combination of THAL and RUX has demonstrated a promising efficacy signal in this initial analysis of an ongoing phase II study, and appears to be well tolerated. Platelet count increases were observed in all patients who entered study with baseline thrombocytopenia, a response which appears to be maintained in the majority of patients observed 6 months after starting combination therapy. As well, anemia responses were observed in 3 of 5 evaluable patients. Collectively, these data indicate a potential role for this regimen in patients with anemia and/or thrombocytopenia, who otherwise have limited treatment options. Updated data on duration of response and overall response of all accrued patients will be presented. Disclosures Rampal: Constellation: Research Funding; Celgene: Honoraria; Incyte: Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Stemline: Research Funding. Verstovsek:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Stein:Celgene: Consultancy; Bayer: Consultancy; Agios: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Kadia:Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Takeda: Consultancy; Celgene: Research Funding; BMS: Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Jazz: Consultancy, Research Funding. Mauro:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Takeda: Consultancy. Pemmaraju:SagerStrong Foundation: Research Funding; daiichi sankyo: Research Funding; novartis: Research Funding; abbvie: Research Funding; cellectis: Research Funding; samus: Research Funding; Affymetrix: Research Funding; stemline: Consultancy, Honoraria, Research Funding; celgene: Consultancy, Honoraria; plexxikon: Research Funding. Bose:Blueprint Medicines Corporation: Research Funding; Astellas Pharmaceuticals: Research Funding; Incyte Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Celgene Corporation: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; CTI BioPharma: Research Funding.

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Phase II Study of Daratumumab in Combination with Azacitidine and Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients Previously Treated with Daratumumab: Darazadex

Blood ◽

10.1182/blood-2020-138869 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 27-28

Author(s):

Swetha Kambhampati ◽

Sandy W. Wong ◽

Thomas Martin ◽

Jeffrey L. Wolf ◽

Priya Choudhry ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Study ◽

Advisory Committees ◽

Refractory Multiple Myeloma ◽

Duration Of Response ◽

Previously Treated ◽

Dose Modifications

Background: Daratumumab, a human anti-CD38 monoclonal antibody, is approved in many countries for use as monotherapy in relapsed/refractory multiple myeloma (RRMM), and in combination with standard-of-care regimens in RRMM. The phase 2 DARAZADEX study will evaluate the efficacy and safety of daratumumab plus azacitidine and dexamethasone in RRMM patients previously treated with daratumumab. Pre-clinical data from our laboratory has demonstrated that azacitidine induces a 1.2 - 2.4 increase in CD38 median fluorescent intensity (MFI) in a dose-dependent manner across four different MM cell lines. (Figure 1A) Using an immortalized transgenic natural killer (NK) cell line to mediate lysis, we observed a significant increase in antibody-dependent cell-mediated cytotoxicity (ADCC) in the azacitidine-treated MM cells as opposed to control. Importantly, this increase in ADCC correlated with CD38 MFI upregulation. (Figure 1B). Based on this data we hypothesize that azacitidine, by upregulating the expression of CD38, can potentially increase the ADCC and efficacy of daratumumab on multiple myeloma cells and help reverse daratumumab resistance. Methods: In this single-arm, 2-stage, phase II study, approximately 23 RRMM patients in the United States will be treated with combination of daratumumab, azacitidine, and dexamethasone. Eligible patients must have progressed on ≥2 lines of prior therapy, including an immunomodulatory drug (IMiD) and proteasome inhibitor, and have previously been treated with daratumumab with most recent daratumumab treatment being at least 6 months prior to enrollment to allow for CD38 normalization. Patients who were previously primary refractory to daratumumab will be excluded from the study. Patients will receive azacitidine at the standard 75 mg/m2 dose 5 days consecutively every 4 weeks starting day -7 to day -3 of Cycle 1 and then Day 22-26 of Cycle 1-3, and subsequently Day 1-5 of Cycle 5 and thereafter until disease progression or intolerance, with dose modifications for toxicities. Daratumumab will be administered intravenously at the standard dose of 16 mg/kg, with first dose administered on day 1. Daratumumab will be dosed in standard fashion: weekly for 8 doses (induction phase), every two weeks for 8 doses (consolidation phase), and then every 4 weeks thereafter (maintenance phase). Daratumumab will be switched to the subcutaneous formulation at a later timepoint. There will be no dose modifications for daratumumab. Dexamethasone at a dose of 40 mg PO (or IV if PO is not available) will be given weekly for Cycle 1 and 2, after which the pre-infusion medication dose can be reduced to 20 mg and non-pre-infusion dose can be reduced or stopped based on investigator's discretion. Bone marrow biopsies will be done within 14 days prior to Cycle 1 day -7 (first azacitidine dose) and on Cycle 1 day 1 prior to first daratumumab infusion (or after completion of first 5 days of azacitidine and prior to first daratumumab infusion), for correlative studies. (Figure 1C) Simon's minimax two-stage design will be used with a safety lead-in cohort of 6 patients. In the first stage, a total of 13 patients will be enrolled (including the safety cohort), and if there is ≥2 responses in 13 patients the study will enroll an additional 10 patients; if there is ≤ 1 responses in 13 patients the study will be stopped. Primary objective is to evaluate the efficacy, as determined by the overall response rate (ORR) of this combination. Secondary objectives include duration of response per international myeloma working group (IMWG) criteria, safety and toxicity, and the 1-year OS and PFS of this combination. An additional secondary objective is to evaluate the changes in CD38 expression on plasma cells induced by azacitidine in patients with RRMM and identify any correlation of this change with depth and duration of response. The exploratory objective will be to evaluate the tumor microenvironment changes induced by azacitidine via mass cytometry (CyTOF). NCT04407442. Figure 1 Disclosures Wong: Bristol Myers Squibb: Research Funding; GSK: Research Funding; Janssen: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Roche: Research Funding; Fortis: Research Funding. Martin:Janssen: Research Funding; GSK: Consultancy; Seattle Genetics: Research Funding; Sanofi: Research Funding; AMGEN: Research Funding. Wolf:Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Shah:GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy; BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding. OffLabel Disclosure: Azactidine is being used off-label in multiple myeloma

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Phase I/II Trial Of Everolimus, Bortezomib and Rituximab In Relapsed Or Relapsed/Refractory Waldenstrom's Macroglobulinemia

Blood ◽

10.1182/blood.v122.21.4402.4402 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4402-4402 ◽

Cited By ~ 3

Author(s):

Irene M. Ghobrial ◽

Erica N Boswell ◽

Stacey Chuma ◽

Ranjit Banwait ◽

Courtney Hanlon ◽

...

Keyword(s):

Partial Response ◽

Phase I ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Study ◽

Complete Response ◽

Recommended Dose ◽

Advisory Committees ◽

Grade 3

Abstract Introduction The phase I aimed to determine the safety and maximum tolerated dose of the combination of everolimus and rituximab, or everolimus, bortezomib, and rituximab and the phase II study aimed to examine response and safety of the combination of all 3 agents in relapsed and/or relapsed/refractory Waldenstrom Macroglobulinemia. This trial was based on our preclinical studies that demonstrated synergistic activity of everolimus and bortezomib with rituximab in WM. Methods Eligibility criteria include: 1) patients with relapsed or relapsed/refractory WM with any number of prior lines of therapy, including everolimus and bortezomib 2) not completely refractory to rituximab 3) measurable disease by monoclonal IgM protein in the serum and lymphoplasmacytic cells in the bone marrow, 4) Not receiving chemotherapy > 3 weeks, or biological/novel therapy for WM > 2 weeks. A cycle is 28 days and a total of 6 cycles are given, followed by everolimus maintenance until Progression. The phase I trial included two stages with a total of four dose levels. In stage A, patients received everolimus at the recommended dose orally daily for 28 days and rituximab at the recommended dose IV on days 1, 8, 15, and 22 every 28 days at cycle 1 and 4 only. In stage B, patients received everolimus at the recommended dose orally daily for 28 days, bortezomib at the recommended dose IV on days 1, 8, 15 every 28 days, and rituximab at the recommended dose IV on days 1, 8, 15, and 22 every 28 days at cycle 1 and 4 only. For the phase II study, patients received everolimus 10 mg daily, bortezomib IV 1.6mg/m2 on days 1, 8, 15 every 28 days, and rituximab 375mg/m2 IV on days 1, 8, 15, and 22 every 28 days at cycle 1 and 4 only. Patients were assessed for response after every cycle. Subjects who had a response continued on therapy for a total of 6 cycles, and then continued on to maintenance therapy with everolimus alone until progression Results Forty-Six patients were enrolled in this phase I/II clinical trial from April 2009 to July 2013. The median age is 65 (range, 47–84) yrs and the median lines of prior therapy is 5 (range, 1–9) with 45 (98%) patients receiving prior rituximab and 23 (50%) receiving prior bortezomib. The median number of cycles on therapy was 19.5 (range, 0–39). Overall, this combination therapy is very well tolerated. Grade 4 toxicities included: neutropenia (4.3%), leukopenia (2.2%), thrombocytopenia (13%), lymphopenia (2.2%) and hypertriglyceridemia (2.2%). Grade 3 toxicities included: neutropenia (13%), leukopenia (13%), anemia (10.9%), lymphopenia (8.7%), pneumonitis (4.3%), SGPT (4.3%), neuropathy (4.3%), Herpes zoster reactivation (4.3%), (2.2%) bacterial endocarditis, (2.2%) congestive heart failure, (2.2%) hearing loss, hyperglycemia (4.3%) hypernatremia (4.3%) and 1(2.2%) subject had an incarcerated inguinal hernia with small bowel obstruction. Two patients discontinued therapy due to grade 3 anemia. For the phase II study, sixteen patients are currently evaluable for response, including 2 (13%) complete response (CR), 11 (68%) partial response and 1 (6%) minimal response (MR), for an overall response rate including MR of 14/16 (88%) in this relapsed/refractory population. Furthermore, overall response including MR in phase I was 1/23 (4%) complete response, 7/23 (30%) partial response and 10/23 (43%) minimal response. In phase II 1/23 (4%) complete response, 14/23 (61%) partial response and 2/23 (9%) minimal response. Additionally, 8 (17%) patients achieved stable disease. Conclusions The combination of everolimus, bortezomib, and rituximab is generally well tolerated, and importantly no grade 3/4 neuropathy was seen. The responses observed to date indicate that this combination is highly effective in this relapsed/refractory population. This study was supported from the FDA Office of Orphan Products Development and by Millennium/Takeda and Novartis Inc. Disclosures: Ghobrial: Onyx: Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees; BMS: Research Funding; Sanofi: Research Funding; Novartis: Membership on an entity’s Board of Directors or advisory committees. Richardson:Millennium: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees. Treon:Millennium: Consultancy. Matous:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau.

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