A Phase II Study of the Combination of Oral Rigosertib and Azacitidine in Patients with Myelodysplastic Syndromes (MDS)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 910-910 ◽  
Author(s):  
Shyamala C. Navada ◽  
Lewis R. Silverman ◽  
Katherine P. Hearn ◽  
Rosalie Odchimar-Reissig ◽  
Erin P. Demakos ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Phase Ii ◽  
Research Funding ◽  
De Novo ◽  
Standard Dose ◽  
Single Agent ◽  
Leukemic Cells ◽  
Bone Marrow Blast ◽  
Recommended Phase Ii Dose

Background: Rigosertib (RIG) is a Ras-mimetic that inhibits the PI3K and PLK cellular signaling pathways by binding directly to the Ras-binding Domain found in Ras effector proteins. It has been tested as a single agent in patients (pts) after failure of hypomethylating agents (HMAs). In vitro, the combination of RIG with azacitidine (AZA) inhibits growth and induces apoptosis of leukemic cells in a sequence-dependent fashion (RIG administered prior to AZA) (Skidan et al 2006). Phase I results of this study in pts with MDS or AML showed combination of oral RIG and standard-dose AZA to be well-tolerated with evidence of efficacy (Navada et al, Blood 2014). Phase II was initiated to further study the combination in pts with MDS. Methods: Results from pts in Phase II with MDS previously untreated with an HMA, or who had failed to respond to or progressed on a prior HMA, are presented, while response data from Phase I MDS pts are updated. Pts with CMML are analyzed separately. Oral RIG was administered twice daily on Day 1-21 of a 28-day cycle at the recommended Phase II dose (RPTD: 560 mg qAM and 280 mg qPM). AZA 75 mg/m2/d SC or IV was administered for 7 days starting on Day 8. A CBC was performed weekly and a bone marrow aspirate and/or biopsy was performed at baseline, day 29, and then every 8 weeks thereafter. Results: The combination of oral RIG and AZA has been administered to a total of 45 pts within Phase I (N=18) and Phase II (N=27). Pts were classified into the following MDS risk categories per the IPSS (Greenberg et al, Blood 1997): intermediate-1 (4), intermediate-2 (10), high-risk (14), and IPSS classification pending (4). Five pts had CMML and 8 had AML. Median age was 66 years; 69% of pts were male; and ECOG performance status was 0, 1, and 2 in 27%, 67%, and 6%, respectively. Twelve pts [MDS (9), CMML (3)] received prior HMA therapy: AZA (11 pts), decitabine (1 pts). Patients have received 1-21+ cycles of treatment to date (median, 3 cycles), with median duration of treatment of 14 weeks. Among 15 evaluable MDS pts treated with the RPTD (1 pt in Phase I, 14 pts in Phase II), marrow responses were observed in 10: marrow CR (mCR) (8), marrow PR (mPR) (2). Responses according to IWG criteria were observed in 10 pts: complete remission (CR) (1), mCR (7), hematologic improvement (HI) (2). Table 1. Responses for MDS Patients Treated at the Recommended Phase II Dose Pt Prior HMA Best BMBL at Nadir1 IWG Response2 Hematologic Improvement 102-008 None mCR mCR Platelet 101-010 None mCR CR Erythroid & Neutrophil 101-011 None mCR mCR None 101-013 None mCR mCR Erythroid 102-010 None SD SD None 101-014 AZA PD PD None 102-011 AZA mPR HI Erythroid & Platelet 101-016 AZA SD SD None 101-017 AZA mCR mCR None 102-013 None NE NE NE 101-019 None SD SD None 101-021 None PD PD None 101-024 None mCR mCR None 101-022 AZA mCR mCR None 101-025 None mCR mCR None 101-026 AZA NE NE NE 101-027 None NE NE NE 102-016 None mPR HI Platelet 1 Silverman et al, Hematol Oncol 2014 2 IWG = International Working Group (Cheson et al, Blood 2006) NE = not evaluable BMBL = bone marrow blast Overall, in pts with MDS treated on Phase I and Phase II, marrow responses were observed in 15 out of 20 evaluable pts: mCR (13), mPR (2). Responses according to IWG 2006 criteria were observed in 14 out of 19 evaluable MDS pts: CR (2), mCR (10), HI (2). Among the 7 evaluable pts with MDS in both the Phase I and Phase II who had failed to respond or progressed on prior treatment with an HMA, 5 had a response after RIG was added: CR (1), mCR (3), HI (1). Analyzed as a separate subgroup, 2 out of 5 (40%) pts with CMML had a mCR. The most frequent adverse events (AEs) in Cycle 1 included nausea (21%) and fatigue (15%), which were also the most frequent AEs in all cycles (fatigue, 28%; nausea, 26%). Six deaths have been observed so far. Three pts were treated for more than 1 year and continue on study. Conclusions: The combination oforalrigosertib and standard-dose AZA was well tolerated in repetitive cycles in pts with MDS. Marrow CR was observed in 65% of pts, both with de novo MDS and after failure of prior HMA therapy. In pts who received the RPTD, 67% of pts with MDS had a bone marrow blast and IWG response. These results suggest potential synergistic interaction of the combination and support continued study of this unique combination in patients with MDS. Disclosures Silverman: Onconova Therapeutics Inc: Honoraria, Patents & Royalties: co-patent holder on combination of rigosertib and azacitdine, Research Funding. Daver:ImmunoGen: Other: clinical trial, Research Funding. DiNardo:Novartis: Research Funding. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Fenaux:CELGENE: Honoraria, Research Funding; JANSSEN: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding. Fruchtman:Onconova Therapeutics Inc: Employment. Azarnia:Onconova Therapeutics Inc: Employment.

A Phase I/II Study of the Combination of Oral Rigosertib and Azacitidine in Patients with Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3252-3252 ◽  
Author(s):  
Shyamala C. Navada ◽  
Guillermo Garcia-Manero ◽  
Francois Wilhelm ◽  
Katherine Hearn ◽  
Rosalie Odchimar-Reissig ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Stable Disease ◽  
Blood Count ◽  
Single Agent ◽  
Complete Response ◽  
Leukemic Cells ◽  
Cell Transplant ◽  
Transfusion Requirements ◽  
Count Recovery

Abstract Background:Rigosertib is a small molecule anti-cancer agent targeting PI3/polo-like kinase pathways that promotes G2/M arrest and has effects on the B-Raf and Ras pathways. It is currently being tested as a single agent with the intravenous (IV) formulation in patients (pts) who have relapsed or are refractory to hypomethylating agents (HMAs) as well as with the oral formulation in lower-risk, red-cell transfusion-dependent MDS patients. Azacitidine (AZA) is first-line therapy for pts with higher-risk MDS. In vitro, the combination of rigosertib with AZA acts synergistically to inhibit growth and induce apoptosis of leukemic cells (Skidan et al 2006). This effect appears to be sequence dependent, requiring exposure to rigosertib first, followed by AZA. These nonclinical results provided the rationale to combine the 2 agents in a phase I/II study in pts with MDS and AML. Methods: Pts with MDS and non-proliferative AML, who were previously untreated or had failed or progressed on an HMA were included in the phase I component of the study. Oral rigosertib was administered twice daily from day 1 through day 21 of a 28-d cycle. AZA 75 mg/m2/d was administered for 7 days starting on day 8 of the 28-d cycle. Pts were entered in 3 escalating-dose cohorts of rigosertib in a classic 3+3 design: [1] 140 mg twice daily; [2] 280 mg twice daily; [3] 560 mg qAM and 280 mg qPM. A CBC was performed weekly and a bone marrow (BM) aspirate and/or biopsy was performed at baseline and every 4-8 weeks afterwards. Results: Eighteen pts have been treated with the combination of oral rigosertib and AZA. Pts had diagnoses of intermediate-1 MDS (3), intermediate-2 MDS (6), high-risk MDS (2), CMML (1), and AML (6); median age was 70.5 years; 61% of pts were male. Pts have received 1-10+ cycles of treatment with the total number of cycles administered thus far being 58. Cytogenetic profiles by IPSS were good (8 pts), poor (8 pts), and intermediate (2 pts). 11of 18 patients were transfusion dependent at baseline [RBC (11), platelet (6)]. One patient became RBC transfusion independent after 3 cycles of treatment. 5 additional patients have had a reduction in their RBC and platelet transfusion requirements. 56% of patients received prior treatment with HMAs: AZA (6 pts), decitabine (4 pts). The most frequent adverse events (AEs) in Cycle 1 included constipation, diarrhea, nausea, fatigue, hypotension, and pneumonia. The AEs did not differ significantly among the 3 cohorts. Elevation in creatinine in 1 pt in cohort 1 was a possibly related grade 3 dose-limiting toxicity that required subsequent expansion of the cohort. Drug-related dysuria/cystitis was not reported in this pt population. Responses according to IWG 2006 criteria were observed in the BM and peripheral blood: Complete Response (CR) (1 pt), Cri (CR with incomplete blood count recovery) (4 pts), stable disease (2), hematologic improvement-erythroid (1). Six pts received fewer than 4 cycles of treatment and are too early to evaluate. Six pts came off study for the following reasons: progression of disease (1), pt request (1), death from pneumonia (2), received stem cell transplant (1), persistent fungal pneumonia (1). Two evaluable pts have responded to the combination after progression or failure on HMA alone. Conclusions: The combination oforalrigosertib at 560/280 mg BID (recommended phase II dose) and standard-dose AZA can be safely administered and appears to be well tolerated in repetitive cycles in pts with MDS and non-proliferative AML. The AE profile does not differ significantly from that of AZA alone. Data from the Phase I component of this study suggest activity in patients with MDS after HMA failure. Additional data are required to evaluate this observation. The Phase II segment of this study is underway to further assess the response of the combination. Table Patient ID Diagnosis Prior HMA % Blasts in BM at Baseline % Blasts in BM after Treatment IWG Response 1 MDS No 2 1 CRi 2 AML No 40 0 CRi 3 AML No 22 N/A NE 4 MDS Azacitidine 0 0 NE 5 AML No 59 N/A NE 6 MDS No 21 <5 CRi 7 MDS No 2 1 CR 8 MDS No 2.5 2 SD 9 AML Decitabine 25 N/A NE 10 MDS Decitabine 12 3 CRi 11 CMML Azacitidine 2 3 SD 12 MDS Azacitidine 4 1 HI-E 13 AML Azacitidine 47 40 TE 14 AML Decitabine 7 7 TE 15 MDS No 9 5 TE 16 AML No 25 6 TE 17 AML No 15 19 TE 18 AML Azacitidine 64 45 TE IWG = International Working Group CR = Complete Response CRi = Complete Response with incomplete blood count recovery NE = Not Evaluable SD = Stable Disease HI-E = Hematologic Improvement - Erythroid TE = Too Early Disclosures Wilhelm: Onconova Therapeutics, Inc: Employment, Equity Ownership. Demakos:Onconova: Consultancy. Azarnia:Onconova Therapeutics, Inc: Employment. Silverman:Onconova: with Icahn School of Medicine at Mount Sinai Patents & Royalties.

The Combination of Quizartinib with Azacitidine or Low Dose Cytarabine Is Highly Active in Patients (Pts) with FLT3-ITD Mutated Myeloid Leukemias: Interim Report of a Phase I/II Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1642-1642 ◽  
Author(s):  
Waleed Abdelall ◽  
Hagop M. Kantarjian ◽  
Gautam Borthakur ◽  
Guillermo Garcia-Manero ◽  
Keyur P. Patel ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Research Funding ◽  
Low Dose ◽  
Response Rate ◽  
Highly Active ◽  
Flt3 Inhibitor ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Low Dose Cytarabine

Abstract Background: FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation in acute myeloid leukemia (AML) is associated with early relapse and poor survival. Quizartinib inhibits FLT3 kinase activity potently and selectively. In phase I and II studies, the composite response rate (CRR) was approximately 50% among patients with FLT3-ITD. There is in-vitro synergy between quizartinib and 5-AZA or LDAC. We hypothesize that adding quizartinib to a hypomethylating agent- such as 5-azacitidine (AZA) -or to cytarabine may improve the response rate expected from the use of either agent alone. Objectives: The primary objective of phase I is to determine dose limiting toxicity (DLT) and maximally tolerated dose (MTD) of combination of quizartinib with either AZA or low-dose cytarabine (LDAC); for phase II is to determine the clinical activity of both combinations. This planned interim analysis reports on the recommended phase II dose (RP2D) and first futility analysis. Methods: For phase I, pts with relapsed/refractory high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) or AML were eligible irrespective of FLT3 mutation and salvage status. For phase II: presence of FLT3-ITD is a requisite, pts must be >60 years with untreated MDS/CMML/AML or any age receiving first salvage treatment. Other requisites: performance status ECOG ≤2, adequate organ function and normal electrolytes (potassium, calcium and magnesium). Important exclusions include: QTcF> 450 msec, administration of drugs that prolong QT/QTc interval or strong CYP3A4 inhibitors or inducers; with the exception of antibiotics, antifungals, and antivirals that are used as standard of care. Treatment cycle is 28 days and comprises of AZA 75 mg/m2 subcutaneously (SQ) or intravenously (IV) for 7 days of every cycle, or cytarabine 20 mg SQ twice daily for 10 days of every cycle along with quizartinib at two planned dose levels: 60 mg (dose level 1) or 90 mg orally daily (dose level 2), uninterrupted. Patients are assigned to AZA or LDAC arm by physician choice or slot availability. Planned accrual for each arm in phase II is 26 pts each and an ORR of ≥50% will be considered favorable. Accrual of 26 pts will give a 95% credible interval for ORR of (0.32, 0.68). The study will be stopped for toxicity (>30%) and/or futility (ORR <50%) at interim analysis for each arm. Results: Fifty-two (Phase I=12, phase II=40) pts have been enrolled: 38 to AZA arm and 14 to LDAC arm. Median age is 67 years (range, 23-83 years), 24 (46%) are female. Cytogenetics are diploid=24, +8=5, monosomy 7=3, miscellaneous=17, 11q=2 and t(8;21)= 1. Median number of prior therapies is 1 (range, 0-7); 7 patients had received prior FLT3 inhibitor: sorafenib (5), crenolanib (1), quizartinib (1). For both combinations quizartinib 60 mg daily was identified as the recommended phase II dose (RP2D). Thirty-five Pts [8 in LDAC arm (23%) and 27 in AZA arm (77%)] of total 52 have responded with ORR 67 % (CR=8, CRp=7, CRi=18, PR=2); all with FLT3-ITD mutation without D835 mutation. ORR is 73% among pts with FLT3-ITD (N=48). Three of eight pts (38%) with prior FLT3 inhibitor exposure responded. Median time to response is 35 days (range, 14-187days). Among responders, two pts died (in CRi=1, PR=1): one with GI bleed and one with progressive pneumonia. Twelve responders discontinued therapy: 11 to receive a SCT and 1 due to loss of response with emergence of D835 mutation. Fifteen responders (CR=2, CRi=8, CRp=3, PR=2) had >50% reduction of FLT3-ITD allelic burden and eight additional pts (CR=5, CRi=1, CRp=2) had no detectable FLT3-ITD at response. The median survival was: 14.8 mo for the total study group: 7.5 mo for LDAC arm and not reached for AZA arm; median EFS has not been reached for either arm (Figure). Treatment emergent grade 3/4 toxicities irrespective of attribution include hypokalemia (15), hypotension (7), hypophosphatemia (7), hyponatremia (7), hypocalcemia (7), hyperbilirubinemia (1), elevated ALT (5), hypernatremia (2) hyperglycemia (1), QTcF prolongation (1, grade 3). Conclusion: Combination of quizartinib and AZA or LDAC is highly active among patients with AML/MDS/CMML with FLT3-ITD mutation in absence of D835 mutation. Response rates appear higher than expected with either agent alone. Clinically significant QTcF prolongation is infrequent. Accrual to the study continues. Figure Figure. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Konopleva:Calithera: Research Funding; Cellectis: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

A Phase I/II Trial of Ixazomib (Ix), Pomalidomide (POM), and Dexamethasone (DEX), in Relapsed/Refractory (R/R) Multiple Myeloma (MM) Patients: Responses in Double/Triple Refractory Myeloma and Poor Risk Cytogenetics

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3316-3316 ◽  
Author(s):  
Amrita Krishnan ◽  
Prashant Kapoor ◽  
Joycelynne Palmer ◽  
Ni-Chun Tsai ◽  
Shaji Kumar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Phase I ◽  
Research Funding ◽  
Standard Dose ◽  
Single Agent ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Refractory Disease ◽  
Poor Risk

Abstract Triplet regimens combining an immunomodulatory agent, a proteasome inhibitor (PI), and a steroid are used to treat newly diagnosed and relapsed multiple myeloma (MM). Although ixazomib (Ix), an oral PI with single agent activity, can be combined with lenalidomide (LEN), patients (pts) with relapsed/refractory (R/R) MM are often LEN-refractory. Pomalidomide (POM) has single agent activity in LEN-refractory disease, and both POM and Ix also show activity in poor cytogenetic risk pts. Methods: Primary objectives: 1) determine the maximum tolerated dose (MTD) of Ix in combination with standard dose POM and dexamethasone (DEX), and 2) evaluate the anti-tumor activity of the triplet. The treatment regimen included two dose levels (3 mg and 4 mg) of Ix on days 1, 8, 15; POM 4 mg days 1-21; and DEX 40 mg days 1, 8, 15, 22, of a 28 day cycle. Eligibility: R/R MM after >1 prior therapy, LEN-refractory, and ≤ grade(gr) 1 peripheral neuropathy (PN). Pts were treated until progression or unacceptable toxicity. Design: Phase I study utilizing a standard 3+3 design; dose limiting toxicities (DLTs) defined during cycle 1. Results: 32 pts treated, 31 evaluable for toxicity and response. Pts received a median 4 cycles (range 1-13); median follow-up is 5.5 months (range 1.8-21.1). Six pts treated on DL1, 25 treated on DL2, the MTD/Phase II dose (P2D). Median age: 62 years (range 38-84); median time from diagnosis: 3.7 years (range 1.0-8.9); median number prior therapies: 3 (range 1-5); prior transplant: n = 23 (74%); double (LEN/Bortezomib[BOR]) or triple (LEN/BOR/Carfilzomib[CFZ]) refractory: 19 (61%). Phase I: DL1 expanded to n=6 after 1/3 pts experienced DLT (gr3 lung infection); no further DLT seen on DL 1 or 2. Adverse events (AEs) related to POM and/or Ix: ANC decrease Gr1/2 n=11 (35%), Gr3/4 n=10 (32%), platelet decrease Gr1/2 n=9 (29%), lymphocyte decrease Gr1/2 n=8 (26%), Gr3/4 n=11 (35%), PN Gr1/2 n=9 (29%), no Gr3/4. Response: Phase I and II, n=31 pts treated. ORR: 45% (6 VGPR, 8 PR); Clinical Benefit Rate (CBR): 81% (6 VGPR, 8 PR, 3 MR, 8 SD). In the pts with high risk cytogenetics (7[23%] 1q, 3[10%] 17p, 2[6%] t(4;14)) an ORR of 58% (3 VGPR, 4 PR) was seen, and the CBR was 83%. In the double or triple refractory pts, an ORR of 26% and CBR of 79% (1 VGPR, 4 PR, 3 MR, 7 SD) were observed. Conclusions: Ix/POM/DEX is a well-tolerated oral combination therapy, and responses were seen even at DL1 and in high risk patients, including those with poor-risk cytogenetics or advanced refractory disease. Disclosures Kapoor: Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Kumar:Millennium: Consultancy, Research Funding; AbbVie: Research Funding; Glycomimetics: Consultancy; Sanofi: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy; Kesios: Consultancy; Onyx: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding. Lonial:Novartis: Consultancy; BMS: Consultancy; Janssen: Consultancy; Merck: Consultancy; Celgene: Consultancy; Onyx: Consultancy; Novartis: Consultancy; BMS: Consultancy; Celgene: Consultancy; Millenium: Consultancy; Janssen: Consultancy; Onyx: Consultancy. Nathwani:Carevive Systems, Inc.: Research Funding. Forman:Mustang Therpapeutics: Other: Construct licensed by City of Hope. Berdeja:Abbvie, Acetylon, Amgen, Bluebird, BMS, Calithera, Celgene, Constellation, Curis, Epizyme, Janssen, Karyopharm, Kesios, Novartis, Onyx, Takeda, Tragara: Research Funding.

Combination of Oral Rigosertib and Injectable Azacitidine in Patients with Myelodysplastic Syndromes (MDS): Results from a Phase II Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3167-3167 ◽  
Author(s):  
Shyamala C. Navada ◽  
Guillermo Garcia-Manero ◽  
Katherine P. Hearn ◽  
Rosalie Odchimar-Reissig ◽  
Erin P. Demakos ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Median Time ◽  
Phase Ii ◽  
Median Duration ◽  
Clinical Benefit ◽  
Research Funding ◽  
Standard Dose ◽  
Advisory Board ◽  
Treatment Naïve ◽  
Clinical Benefit Response

Abstract Background: Based on a model suggesting leukemia can be driven by combined effect of mutations in an epigenetic gene (DNMT3) and Ras, the combination of a hypomethylating agent (HMA) such as azacitidine (AZA) and a Ras mimetic such as rigosertib (RIG) may have enhanced activity in both MDS and AML. The mechanism of action for RIG (Athuluri-Divakar et al, Cell 2016) documents its interference with the RAS-binding domains of RAF kinases and inhibition of the RAS-RAF-MEK and the PI3Ks pathways. In vitro, the combination of RIG with AZA was found to act synergistically to inhibit growth and to induce apoptosis of leukemic cells in a sequence-dependent manner (exposure to RIG first, followed by AZA) (Skidan et al, AACR 2006). Rigosertib's low bone marrow toxicity in pre-clinical assays, effective inhibition of human hematopoietic tumor cell lines, and its synergy with AZA suggests the potential value of combination treatment for patients (pts) with MDS. Phase I results of the current clinical study in pts with MDS or AML showed the combination of oral RIG and standard-dose AZA to be well-tolerated with evidence of efficacy (Navada et al, Blood 2014). The phase II portion of the study was initiated to further evaluate the combination in pts with MDS. Methods: Phase II results are presented for HMA-treatment-naïve MDS pts and for those with MDS failing to respond to or progressed on a prior HMA. Oral RIG was administered twice daily on Day 1-21 of a 28-day cycle at the recommended Phase II dose (RPTD: 560 mg qAM and 280 mg qPM). AZA 75 mg/m2/d SC or IV was administered for 7 days starting on Day 8. A CBC was performed weekly and a bone marrow aspirate and/or biopsy were performed at baseline, D29, and then every 8 weeks thereafter. Results: The combination of oral RIG and injectable AZA has been administered to a total of 54 pts, of whom 40 were pts with MDS including HMA-treatment-naïve (N=23) and previously HMA treated pts (N=17). Median age was 66 years (range 25-85); 73% of pts were male; and ECOG performance status was 0, 1, and 2 in 23%, 73%, and 5%, respectively. 17 pts received prior HMA therapy: 12 AZA, 4 decitabine, and 1 both. Patients have received 1-36+ cycles of treatment (median, 6 cycles), with a median duration of treatment of 25 weeks (range 4 to 145+ weeks). 8 (20%) and 2 (5%) of pts have been treated for more than 1 and 2 years, respectively. Table 1 shows the response per IWG 2006 criteria (Cheson, Blood 2006) among 33 evaluable patients. The response per IWG 2006 was complete remission (CR) in 8 (24%), concurrent marrow CR and hematologic improvement (HI) in 9 (27%), marrow CR alone in 7 (21%), and HI alone in 1 (3%). When overall response is defined as CR plus PR plus HI - responses with improvement in marrow function and thus either normalization of the peripheral blood count or lineage improvement - defined here as Clinical Benefit Response - 55% of all evaluable pts and 70% of the evaluable HMA-treatment-naïve patients showed responses meeting these criteria. Median time to initial response was 2 cycles (2.2 months), and median time to best response was 3 cycles (3.3 months). Median duration of response was 8 months for CR, 14.3 months for marrow CR, 7.4 months for erythroid response, 8 months for platelet response, and 6.2 months for neutrophil response. Clinical response is classified by IPSS-R risk categories below. The most frequently reported adverse events are nausea (41%), fatigue (39%), diarrhoea (37%), constipation (37%), dysuria (28%), decreased appetite (28%), haematuria (24%, 8% Grade 3), pyrexia (24%), dizziness (22%), thrombocytopenia (20%), back pain (20%), dyspnoea (20%), and cough (20%). Eight deaths were reported on study with most common causes including infection and progression of disease. Conclusions: The combination oforalRIG and standard-dose AZA was well tolerated in repetitive cycles in pts with MDS. Response per IWG 2006 criteria was observed both in HMA-treatment-naïve patients (85%) and in patients after failure of prior HMA therapy (62%); employing Clinical Benefit Response as the criteria, these groups had 70% and 31% response, respectively. These clinical results confirm the preclinical synergistic interaction with the combination of RIG and AZA reported by Skidan et al, and suggest that the combination can overcome clinical resistance to HMAs. Based on these results, a Phase III study of the combination of oral RIG and AZA in patients with MDS is planned. Disclosures Navada: Onconova Therapeutics, Inc.: Research Funding. Daver:Karyopharm: Honoraria, Research Funding; Pfizer: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Ariad: Research Funding; Otsuka: Consultancy, Honoraria; Kiromic: Research Funding; BMS: Research Funding. DiNardo:Agios: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. Fenaux:Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding. Petrone:Onconova Therapeutics, Inc.: Employment. Zbyszewski:Onconova Therapeutics, Inc.: Employment. Fruchtman:Onconova: Employment. Silverman:Onconova Therapeutics, Inc.: Patents & Royalties: Co-Patent holder for the combination of azacitidine and rigosertib, Research Funding.

First-in-human phase I/II clinical trial of ONC-392: Preserving CTLA-4 immune tolerance checkpoint for safer and more effective cancer immunotherapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3159-TPS3159
Author(s):  
Christian Diego Rolfo ◽  
Soren Bentzen ◽  
Martin Devenport ◽  
Yang Liu ◽  
Pan Zheng
Keyword(s):  
Clinical Trial ◽  
Tumor Microenvironment ◽  
Cancer Immunotherapy ◽  
Phase Ii ◽  
Standard Dose ◽  
Single Agent ◽  
Stage Iv ◽  
Dose Finding ◽  
Treg Depletion ◽  
Recommended Phase Ii Dose

TPS3159 Background: A major paradigm in cancer immunotherapy is to use checkpoint inhibitors to break regulatory mechanisms that guard the host against autoimmune diseases. CTLA-4-targeting immunotherapy was the first example to establish this paradigm. However, the clinically tested anti-CTLA-4 antibodies exhibit suboptimal efficacy but high toxicity. Our recent studies have demonstrated that immunotherapy-related adverse events (irAE) and the cancer immunotherapeutic effect (CITE) represent distinct and therapeutically separable activities of anti-CTLA-4 antibodies. The irAEs are attributable to inactivation of the CTLA-4 checkpoint, while the CITE is effective through selective depletion of regulatory T cells (Treg) in the tumor microenvironment. We hypothesize that a safer and more effective CTLA-4-targeting immunotherapy should preserve the CTLA-4 checkpoint while enhancing the efficacy and selectivity of Treg-depletion in tumor microenvironment. In preparation to test this ground-breaking hypothesis clinically, we have generated a next generation of anti-CTLA-4 antibody that preserves the CTLA-4 immune checkpoint by avoiding lysosomal degradation of CTLA-4. The new antibody, ONC-392, has dramatically lower irAEs in a humanized mouse model and significantly more potent activity in depleting tumor-infiltrating Tregs, resulting in more effective CITE. Methods: This is an open label Phase IA/IB clinical study to test the safety, pharmacokinetics (PK), and efficacy of ONC-392 as a single agent and in combination with Pembrolizumab in advanced solid tumors and non-small cell lung cancer patients. The study consists of two linked parts: Part A is a dose-finding rapid titration study, with ONC-392 as a single agent in patients with advanced disease of various histology. The aim of this trial is to define the recommended Phase II dose for ONC-392 monotherapy (RP2D-M), Part B is a Phase IA/IB trial of ONC-392 in combination with a standard dose of 200 mg Pembrolizumab in patients with NSCLC. The trial consists of a dose-finding, dose escalation or de-escalation, Phase IA component aimed at defining the recommended phase II dose for ONC-392 in combination with a standard dose of Pembrolizumab (RP2D-C), then progressing into two parallel, single arm, Phase IB expansion cohorts to test for safety and initial efficacy in two groups of patients with NSCLC: Stage IV NSCLC anti-PD(L)1 immunotherapy naïve with PD-L1-positive (PD-L1 TPS ≥ 1%); Stage IV NSCLC refractory/resistant to anti-PD(L)1 immunotherapy. Clinical trial information: NCT04140526 .

scholarly journals A Phase I/II Study of NMS-03592088, a FLT3, KIT and CSF1R Inhibitor, in Patients with Relapsed or Refractory AML or CMML

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3855-3855
Author(s):  
Marina Ciomei ◽  
Lucia Zanetta ◽  
Federico Lussana ◽  
Erika Ravelli ◽  
Francesco Fiorentini ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Single Agent ◽  
Dose Titration ◽  
Advisory Committees ◽  
Secondary Resistance ◽  
Support Research ◽  
Refractory Aml

Background: NMS-03592088 is a novel, potent inhibitor of the FLT3, CSF1R and KIT receptor tyrosine kinases (KD < 1 nM for all three targets). The compound demonstrated high preclinical efficacy following oral administration in all tested target-dependent tumor models, including those harboring kinase domain secondary resistance mutations, such us the FLT3 residue 691 gatekeeper mutation and the KIT residue 670 and exon 17 mutations. In a FLT3-ITD model of disseminated AML, efficacy observed following single agent treatment with NMS-03592088 was further significantly increased when administered in combination with cytarabine, with excellent tolerability. In preclinical studies conducted in non-human primates, a dose-related increase of circulating CSF1 levels was observed in association with the administration of NMS-03592088, consistent with in vivo inhibition of CSF1R by the compound, thus providing the opportunity for the use of CSF1 levels as a potential pharmacodynamic biomarker of CSF1R modulation in the clinical setting. All three targets of NMS-03592088 are relevant in different settings of hematologic malignancies and solid tumors. In particular, FLT3 mutations occur in approximately 30% of acute myeloid leukemia patients (AML), and are associated with a poor prognosis; KIT mutations are reported in patients with the core-binding factor (CBF) subtype of AML and the CSF1 and/or CSF1R genes are frequently expressed in AML blasts. Recent experimental evidence suggests a potential therapeutic rationale for CSF1R blockade in AML, possibly due to interference with microenvironmental support [Edwards DK et al, Blood, 2019, 133: 588]. Furthermore, chronic myelomonocytic leukemia (CMML) blasts express high levels of CSF1R and NMS-03592088 was able to effectively inhibit their proliferation, concomitant with the suppression of intracellular CSF1R dependent signalling. A clinical trial exploring safety, tolerability and efficacy of NMS-03592088 in patients with AML and CMML is therefore warranted. Trial design: This first-in-human study (EudraCT Number: 2018-002793-47) is designed as an open-label multicenter Phase I/II trial including patients with relapsed or refractory AML or CMML who have exhausted standard treatment options, or for whom standard therapy is considered unsuitable. The study is designed to characterize the safety, tolerability, pharmacokinetics, pharmacodynamics and to explore the preliminary anticancer activity of NMS-03592088 administered orally as single agent once daily for 21 consecutive days, followed by a 7-day break within a 28 day cycle. The study includes an initial conventional phase I part with an accelerated dose titration design in subsequent cohorts of 3+3 patients aimed at defining the maximal tolerated dose (MTD) and the recommended phase 2 dose (RP2D), followed by a limited dose expansion to confirm the RP2D. Once the RP2D is confirmed, a single-stage exploratory Phase II part will start comprising two parallel cohorts, one cohort will consist of AML FLT3 mutated patients and one of patients with CMML. Patients previously treated with FLT3 inhibitors are allowed to participate. The primary endpoint of the Phase II portion of the study is Overall Response Rate. Efficacy will be assessed according to standard criteria [Döhner H et al, Blood 2017, 129: 424; Savona MR et al., Blood, 2015, 125: 1857]. Exploratory endpoints are included to evaluate the potential effects of treatment with NMS-03592088 on circulating levels of CSF1 in plasma, the potential correlation of cellular CSF1R expression levels with clinical outcome in both AML and CMML, and the mutational status of a panel of leukemia-related genes, not limited to FLT3. The Phase I part started in Italy in March, 2019 and is currently ongoing. Disclosures Ciomei: NMS: Employment. Zanetta:Clioss: Employment. Fiorentini:Accelera: Employment. Bosotti:NMS: Employment. Ardini:NMS: Employment. Lombardi Borgia:NMS: Employment. Pulci:Accelera: Employment. Gatto:Clioss: Employment. Di Sanzo:Clioss: Employment. Colajori:Clioss: Consultancy. Davite:Clioss: Employment. Galvani:NMS: Employment. Gan:NMS: Employment. Rossi:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Mundipharma: Honoraria; BMS: Honoraria; Sandoz: Honoraria; Daiichi-Sankyo: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees. Rambaldi:Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, travel support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Isacchi:NMS: Employment.

scholarly journals Temsirolimus in Combination with Bendamustine and Rituximab for the Treatment of Relapsed Mantle Cell and Follicular Lymphoma: Report on an Ongoing Phase I/II Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3930-3930
Author(s):  
Georg Hess ◽  
Ulrich Keller ◽  
Johannes Atta ◽  
Ulrich Bitz ◽  
Christian Lerchenmueller ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Research Funding ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Response Rates ◽  
Phase Iii ◽  
Mtor Inhibition ◽  
Grade 3 ◽  
Ongoing Phase

Abstract Background: mTOR inhibition has been shown to be effective in various subtypes of malignant lymphomas. In relapsed MCL a phase III trial could prove superiority of Temsirolimus to standard options. Furthermore, in patients with follicular and diffuse large B-cell lymphoma, promising response rates could be observed (Smith et al, JCO 2010). Whereas combination to single agent Rituximab (R) improved efficacy (Ansell et al, Lancet Oncology 2011), there is limited information of the feasibility and efficacy in combination with chemotherapy. Bendamustine (B) has been shown to be effective in various lymphoma entities and has a beneficial side effect profile (Rummel et al, JCO, 2005). In the phase I of this trial, we have established that 50mg of Temsirolimus given 3 times weekly in a four week cycle could be safely added to BR (Hess, Leukemia, 2015). Here we report for the first time combined results of phase I and II of this trial. Methods: this is a multicenter, national, prospective trial. Inclusion criteria: patients were eligible if they had histologically proven FL or MCL, 1-3 prior treatment lines, no curative option available, no refractoriness to Bendamustine, measurable disease, ECOG < 3, sufficient bone marrow reserve, no severe concomitant diseases and given informed consent. Treatment consisted of Bendamustine 90mg/m² day 1-2, Rituximab 375mg/m² day 1 and Temsirolimus 50 mg day 2, 8, 15 of a 28d cycle. A total of 4 cycles was planned with interim staging after 2 cycles. Results: Overall 34 patients (pts) have been included until now (15 pts phase I, 19 pts phase II). Concerning clinical characteristics, median age was 71 years, with 25 MCL and 9FL, and a median number of 2 pretreatments (1-3). Overall the treatment was well tolerated, and toxicity was predominantly hematologic. In 118 evaluable cycles of chemotherapy the following hematologic grade 3 / 4 toxicities were noted: leukopenia (11 pts, 32%), neutropenia (8 pts, 24%), and thrombocytopenia (7 pts, 21%). Non-hematologic grade 3 / 4 observed in at least two patients were angioedema and decrease in blood potassium, infection, metabolic (4 events). AE's of special interest: pulmonary: rate of cough (4; 12%) and pneumonitis (1; 3%); gastrointestinal: diarrhea (6; 18%), nausea (13, 38%); general: fatigue (16; 47%), mucositis (13, 38%); bleeding: epistaxis (4; 12%), which all were predominantly grade 1 or 2. Response: currently, best responses were 8 CR (31%), 16 PR (62%) and 2 SD (8%) in 26 patients evaluable so far. Updated results will be presented at the meeting. Overall responses were 94% in MCL (7 CR, 10 PR, 1 SD) and 88% in FL (1 CR, 6 PR, 1 SD). After a median follow up of 13 months (mean: 21 months) median PFS is 18.6 months for the entire cohort, with 22 months for MCL and not reached in FL. Summary: In this ongoing phase II trial 50mg Temsirolimus (day 1,8,15) in combination with Bendamustine and Rituximab was well tolerated and feasible. A moderate dose of Temsirolimus to standard chemotherapy might be the optimal way to achieve the maximum efficacy with mTOR inhibitors; in fact excellent response rates suggest an additive effect of mTOR inhibition to BR. Even after the BTK inhibitor Ibrutinib has entered the clinical arena of MCL, this combined treatment represents a valuable additional option especially for patients with relapsed MCL Disclosures Hess: Pfizer, Janssen, Roche, Mundipharma: Honoraria, Research Funding; Janssen, Roche, , Celgene, Novartis: Consultancy. Keller:Roche: Consultancy, Honoraria; Pfizer: Consultancy. Witzens-Harig:Roche: Honoraria; Pfizer: Honoraria, Research Funding.

Phase I/II study of erlotinib combined with cisplatin and radiotherapy for locally advanced squamous cell carcinoma of the head and neck (SCCHN)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5575-5575 ◽  
Author(s):  
D. Herchenhorn ◽  
F. L. Dias ◽  
C. G. Ferreira ◽  
M. Bezerra ◽  
A. J. Fonseca ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Residual Disease ◽  
Standard Dose ◽  
Single Agent ◽  
Locally Advanced ◽  
Stage Iii ◽  
Oropharyngeal Carcinoma ◽  
Toxicity Data

5575 Background: Erlotinib has single agent activity in SCCHN. Preclinical data indicates synergy with both cisplatin and radiotherapy (RT). Methods: This phase I/II study included patients (pts) with stages III and IV SCCHN. Pts received therapy with RT 70.2 Gy for 8 weeks and cisplatin (C) 100 mg/m2, 3 doses every 3 weeks, both starting on Day 8. Erlotinib (E) was started on Day 1 and continued until the end of RT. Phase I doses were escalated in cohorts of 3 pts/dose level: level 1–50 mg, level 2–100 mg and level 3–150 mg. In case of grade IV toxicity leading to RT interruption, 3 additional pts were included in the same dose level. Frozen tissue for molecular studies was collected before and after treatment. Results: Phase I was completed with 9 patients. No patient had RT interruption due to grade IV toxicity. Consequently 150 mg/day was established as the phase II dose. Twelve patients have been included in the phase II part of the trial. Final toxicity data is available for 13 patients (9 from phase I and 4 from phase II). Median age was 58 years, 10 pts had laryngeal carcinoma (stage III 4pts, IVA 3 pts, IVB 3 pts) and 3 oropharyngeal carcinoma (stage III 1pt, IVA 1pt, IVB 1 pt). The dose of C was reduced or held in 3 pts due to ototoxicity (2 pts) and neutropenia (1 pt). Other grade III or IV toxicity included dermatitis (8 pts), skin rash (3 pts), respiratory infection (2 pts), nausea (2 pts), neutropenia (2 pts), mucositis (2 pts) and cutaneous infection (1 pt). Response was accessed by direct visualization/biopsy and CT/MRI scans. Among the 13 patients who have completed treatment, 11 (84.6%) achieved complete pathological response, 1 had residual disease and 1 disease progression. Conclusions: This trial establishes the standard dose of erlotinib, 150 mg/day, as safe to be combined with full dose cisplatin and radiotherapy, in locally advanced SCCHN. Accrual for the phase II study is ongoing and additional response and toxicity data will be presented at the meeting. No significant financial relationships to disclose.

A Phase II Study of the MEK 1/2 Inhibitor AZD6244 (Selumetinib, ARRY-142866) in Relapsed or Refractory Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2931-2931
Author(s):  
Beata Holkova ◽  
Ashraf Z. Badros ◽  
Robert Geller ◽  
Peter M. Voorhees ◽  
Adriana Zingone ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Subcutaneous Tissue ◽  
Single Agent ◽  
Mitogen Activated Protein Kinase ◽  
Response Threshold ◽  
Clinical Activity

Abstract Abstract 2931 AZD6244 is a potent, selective, oral, non-ATP competitive small molecule inhibitor of the mitogen-activated protein kinase, MEK 1/2 that has shown significant pre-clinical activity in multiple myeloma (MM) cells, both in vitro and in vivo, as well as a favorable clinical profile. The present phase II study was designed to determine the response rate for AZD6244 in patients with relapsed or refractory MM. The study utilized a two-stage Simon design to allow for early termination if there was strong evidence of regimen inactivity. Eligible patients were restricted to those with MM who have had at least 2 prior regimens. AZD6244 capsules (75 mg) were administered orally twice daily continuously for 28 day cycles. Response was evaluated after 3 cycles. To date, 37 patients have been enrolled (13 in the 1st stage and 24 in the 2nd stage). One subject enrolled in the 1st stage was not treated. Gender enrollment was balanced (male/female 18/19). The median age of treated patients was 65 years [range 43–81]. ECOG performance scores ranged from 0–2. The median number of prior therapies was 5 [range 2–11]. The most common treatment-related adverse events (occurring in 10–50% of patients) were leukopenia, acneiform rash and other skin/subcutaneous tissue manifestations, fatigue, limb edema, increased aspartate aminotransferase (AST), neutropenia, nausea, facial edema, vomiting, thrombocytopenia, increased creatine phosphokinase, and diarrhea. The most common grade 3 and 4 toxicities (CTCAE v4) included fatigue, peripheral sensory neuropathy, increased AST, neutropenia, nausea, hypotension, thrombocytopenia, increased alanine aminotransferase, and diarrhea. Five deaths have occurred: 2 associated with sepsis, 1 associated with acute kidney injury, all deemed possibly related to AZD6244; and 2 due to disease progression after discontinuation of study treatment. Two objective partial responses have been reported, the first of which justified expansion of the study to the 2nd stage. Twelve patients have had a best response of stable disease, 11 patients have had progressive disease, 1 patient withdrew after cycle 1 (unrelated to toxicity) and did not have response assessed, 3 patients died before response was assessed, and 7 patients are too early to evaluate. Accrual is ongoing to determine if the response threshold in the 2nd stage can be met. Correlative studies are ongoing and are designed to identify potential mechanisms of response/resistance to AZD6244, and to determine the effect of AZD6244 on the bone marrow microenvironment. These include, among others, assessment of pre- and post-treatment expression of phospho-MEK 1/2 and -ERK 1/2, and total levels of Bim. Fifteen patients consented to correlative sampling of bone marrow, blood and/or urine. Results and sample analysis are pending. It is concluded that AZD6244 has modest activity as a single agent in relapsed or refractory MM. This trial also provides a foundation for successor studies employing the MEK 1/2 inhibitor AZD6244 in combination with other agents in patients with MM. Disclosures: Voorhees: Pfizer: Research Funding; Centocor Ortho Biotech: Research Funding; Celgene: Research Funding; MedImmune: Consultancy; Merck: Research Funding.

Phase I Trial of the Targeted Alpha-Particle Nano-Generator Actinium-225 (225Ac)-Lintuzumab (Anti-CD33; HuM195) in Acute Myeloid Leukemia (AML)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 768-768 ◽  
Author(s):  
Joseph G. Jurcic ◽  
Todd L. Rosenblat ◽  
Michael R. McDevitt ◽  
Neeta Pandit-Taskar ◽  
Jorge A. Carrasquillo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Clinical Activity ◽  
Bone Marrow Blast ◽  
Elimination Kinetics ◽  
Advisory Committees ◽  
Dose Levels

Abstract Abstract 768 Background: Lintuzumab, a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest activity against AML. To increase the antibody's potency yet avoid nonspecific cytotoxicity seen with β-emitting isotopes, the α-emitter bismuth-213 (213Bi) was conjugated to lintuzumab. Substantial clinical activity was seen in phase I and II trials, but the use of 213Bi is limited by its 46-min half-life. The isotope generator, 225Ac (t½=10 days), yields 4 α-emitting isotopes and can be conjugated to a variety of antibodies using DOTA-SCN. 225Ac-labeled immunoconjugates kill in vitro at radioactivity doses at least 1,000 times lower than 213Bi analogs and prolong survival in mouse xenograft models of several cancers (McDevitt et al. Science 2001). Methods: We are conducting a first-in-man phase I dose escalation trial to determine the safety, pharmacology, and biological activity of 225Ac-lintuzumab in AML. Results: Fifteen patients (median age, 62 yrs; range, 45–80 yrs) with relapsed (n=10) or refractory (n=5) AML were treated to date. Patients received a single infusion of 225Ac-lintuzumab at doses of 0.5 (n=3), 1 (n=4), 2 (n=3), 3 (n=3), or 4 (n=2) μCi/kg (total administered activity, 23–402 μCi). No acute toxicities were seen. Myelosuppression was the most common toxicity; the median time to resolution of grade 4 leukopenia was 26 days (range, 0–71 days). DLT was seen in 3 patients, including myelosuppression lasting >35 days in 1 patient receiving 4 μCi/kg and death due to sepsis in 2 patients treated at the 3 and 4 μCi/kg dose levels. Febrile neutropenia was seen in 4 patients, and 4 patients had grade 3/4 bacteremia. Extramedullary toxicities were limited to transient grade 2/3 liver function abnormalities in 4 patients. With a median follow-up of 2 mos (range, 1–24 mos), no evidence of radiation nephritis was seen. We analyzed plasma pharmacokinetics by gamma counting at energy windows for 2 daughters of 225Ac, francium-221 (221Fr) and 213Bi. Two-phase elimination kinetics were seen with mean plasma t½-α and t½-β of 1.9 and 35 hours, respectively. These results are similar to other lintuzumab constructs labeled with long-lived radioisotopes. Peripheral blood blasts were eliminated in 9 of 14 evaluable patients (64%), but only at doses of ≥1 μCi/kg. Bone marrow blast reductions were seen in 8 of 12 evaluable patients (67%) at 4 weeks, including 6 patients (50%) who had a blast reduction of ≥50%. Three patients treated with 1, 3, and 4 μCi/kg achieved bone marrow blast reductions to ≤5%. Conclusions: This is the first study to show that therapy with a targeted α-particle generator is feasible in humans. 225Ac-lintuzumab has antileukemic activity across all dose levels. Accrual to this trial continues to define the MTD. Disclosures: Jurcic: Actinium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. McDevitt:Actinium Pharmaceuticals, Inc.: Consultancy, Research Funding. Cicic:Actinium Pharmaceuticals, Inc.: Employment, Equity Ownership, Patents & Royalties. Scheinberg:Actinium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

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