Efficacy and Safety of Ruxolitinib and Steroids for Treating Patients with Relapsed or Refractory Multiple Myeloma (RRMM)

Introduction Ruxolitinib (RUX) is an FDA-approved oral, selective inhibitor of Janus kinase (JAK) 1/2 for the treatment of patients with intermediate or high-risk myelofibrosis and polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea. Preclinical studies from our laboratory have demonstrated that RUX in combination with dexamethasone shows marked anti-myeloma effects both in vitro and in vivo. Specifically, RUX blocks expression of Mucin 1 whose function is linked to lenalidomide (LEN) resistance and down-regulates PD-L1 and PD-L2 expression and reduces tumor stimulatory M2 macrophage polarization in multiple myeloma (MM) bone marrow. Recently published results from a Phase 1 trial for 28 heavily previously treated MM patients administered RUX, LEN and methylprednisolone (MP) demonstrated that the therapy was well tolerated and RUX overcame refractoriness to LEN and steroids (Berenson et al., Clin Cancer Res. 2020). The clinical and overall response rates were 46% and 28%, respectively, and all 12 responding patients were refractory to LEN. To further evaluate whether RUX and steroids without LEN demonstrate clinical activity and its tolerability in the same patient population, an ongoing Phase I trial was expanded to also include a cohort of patients treated with this two-drug combination (NCT03110822). Methods MM patients must have failed > 3 prior regimens and have been exposed to a proteasome inhibitor and LEN. Patients were treated orally (PO) with 15 mg RUX twice daily on days 1-28 of a 28-day cycle and 40 mg MP every other day. The treatment of this two-drug combination was continued until disease progression (PD). Once PD was confirmed, LEN at 10 mg PO daily on days 1-21 of a 28-day cycle was added to the regimen. Primary endpoints were safety, clinical benefit rate (CBR) and overall response rate (ORR). Results As of July 25, 2020, 16 of the planned 29 patients have been enrolled, and 15 patients have completed at least 1 full cycle of therapy; and, thus, were evaluable for efficacy. The median age was 64 years (range, 46-77), and 9 (60%) were male. Patients received a median of 4 (range, 3-10) prior treatments including LEN and steroids to which they were all refractory. Of the 15 evaluable patients treated with RUX and steroids, the CBR and ORR were 53% (n=8) and 33% (n=5), respectively. With a median follow-up of 4.7 months, the median duration of response was 3.5 months (range, 1-11+). Five and 2 patients showed stable disease and progressive disease, respectively. Notably, all 8 responding patients were refractory to LEN (i.e. progressed while on or within 8 weeks of last dosage). Of 6 patients who had progressed on the two-drug combination and had LEN added to their regimen, 3 patients responded (2 MR and 1 PR). Four patients experienced SAEs including sepsis (7%), group B strep sepsis with neutropenic fever and nausea (7%), pneumonia and pneumothorax (7%), thrombocytopenia (7%), and hyperglycemia (7%). Two patients died (one each from pneumonia and progressive disease). Conclusions This ongoing phase 1 trial is the first study reporting clinical activity of the JAK inhibitor RUX with steroids for MM. These results demonstrate that RUX with only steroids is also well tolerated and shows promising efficacy for treating heavily previously treated MM patients. Because of this, additional studies are being conducted with higher doses of RUX in combination with MP for this patient population. Disclosures Berenson: Takeda: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Incyte: Honoraria, Patents & Royalties: OncoTracker, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Swift:Jassen: Consultancy, Honoraria, Speakers Bureau; bristol myers squibb: Consultancy, Honoraria, Speakers Bureau; Amgent: Consultancy, Honoraria, Speakers Bureau. Boccia:Incyte: Consultancy, Honoraria, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Rigel: Consultancy, Honoraria, Research Funding, Speakers Bureau. OffLabel Disclosure: Ruxolitinib and steroids only for treatment patients with Multiple Myeloma

Download Full-text

Efficacy and Safety of Ruxolitinib and Steroids for Treating Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2021-151016 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2727-2727

Author(s):

James R. Berenson ◽

Daisy Martinez ◽

Tahmineh Safaie ◽

Noemi Silagan ◽

Jennifer To ◽

...

Keyword(s):

Multiple Myeloma ◽

Drug Combination ◽

Macrophage Polarization ◽

Phase 1 ◽

Janus Kinase ◽

Clinical Activity ◽

M2 Macrophage ◽

Inadequate Response ◽

Phase 1 Trial ◽

Previously Treated

Abstract Introduction Ruxolitinib (RUX) is an FDA-approved oral, selective inhibitor of Janus kinase (JAK) 1/2 for the treatment of patients with intermediate or high-risk myelofibrosis and polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea. Preclinical studies from our laboratory have demonstrated that RUX in combination with dexamethasone shows marked anti-myeloma effects both in vitro and in vivo. Specifically, RUX blocks expression of Mucin 1 whose function is linked to lenalidomide (LEN) resistance, downregulates PD-L1 and PD-L2 expression and reduces tumor stimulatory M2 macrophage polarization in multiple myeloma (MM) bone marrow. Recently published results from a Phase 1 trial for 28 heavily previously treated MM patients administered RUX, LEN and methylprednisolone (MP) demonstrated that the therapy was well tolerated and RUX overcame refractoriness to LEN and steroids (Berenson et al., Clin Cancer Res. 2020). The clinical benefit rate (CBR) and overall response rate (ORR) were 46% and 28%, respectively, and all 12 responding patients were refractory to LEN. We evaluated whether the combination of RUX and steroids without LEN was active for treating similar patients through treatment of a cohort within the current trial using this two-drug combination (NCT03110822). Methods MM patients must have failed > 3 prior regimens and have been exposed to a proteasome inhibitor and LEN. Patients were treated orally (PO) with 15 mg RUX twice daily on days 1-28 of a 28-day cycle and 40 mg MP every other day. The treatment of this two-drug combination was continued until disease progression (PD). Once PD was confirmed, LEN at 10 mg PO daily on days 1-21 of a 28-day cycle was added to the regimen. Primary endpoints were safety, ORR and CBR. Results As of July 15, 2021, 27 patients were enrolled. The median age was 64 years (range, 46-85), and 17 (63%) were male. Patients received a median of 4 (range, 3-11) prior treatments including LEN and steroid-containing regimens to which they were all refractory. Twenty-six patients have completed at least 1 full cycle of therapy; and, thus, were evaluable for efficacy. The ORR and CBR were 35% (n=9) and 39% (n=10), respectively. Notably, all 10 responding patients were refractory to LEN (i.e., progressed while on or within 8 weeks of last dosage). The remaining patients showed stable disease (n=12) or PD (n=4). The median follow-up was 13 months. The median progression-free survival was 4 months (range, 1-21). The median duration of response was 11 months (range, 1-20). Of 13 patients who progressed on the two-drug combination and had LEN added to their regimen, 6 patients responded (3 MR and 3 PR). Nine patients experienced SAEs including sepsis (12%), sepsis with neutropenic fever (4%), thrombocytopenia (4%), hyperglycemia (4%), neutropenia (4%), anemia (4%), acute heart failure (4%), rotator cuff tear (4%), osteomyelitis (4%), aspiration pneumonia (4%), pneumonia and pneumothorax (4%), and deep venous thrombosis (4%). Two patients died (one each from pneumonia and PD). Conclusions This ongoing Phase 1 trial is the first study demonstrating clinical activity of the two-drug combination of the JAK inhibitor RUX with steroids for MM patients. The treatment was well tolerated and shows promising efficacy for treating heavily previously treated MM patients. Because of this, additional studies are being conducted with higher doses of RUX in combination with MP for this patient population. Disclosures Vescio: Janssen: Speakers Bureau; Karyopharm: Speakers Bureau; GlaxoSnithKlein: Speakers Bureau; Amgen: Speakers Bureau. OffLabel Disclosure: Ruxolitinib is being investigated off-label to determine if it shows anti-myeloma activity in combination with steroids for relapsed/refractory myeloma patients.

Download Full-text

Clinical Activity of Duvelisib (IPI-145), a Phosphoinositide-3-Kinase-δ,γ Inhibitor, in Patients Previously Treated with Ibrutinib

Blood ◽

10.1182/blood.v124.21.3335.3335 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3335-3335 ◽

Cited By ~ 13

Author(s):

Pierluigi Porcu ◽

Ian Flinn ◽

Brad S. Kahl ◽

Steven M. Horwitz ◽

Yasuhiro Oki ◽

...

Keyword(s):

Research Funding ◽

Progressive Disease ◽

Resistance Mutation ◽

Hematologic Malignancies ◽

Clinical Activity ◽

Prior Therapy ◽

Best Response ◽

Previously Treated ◽

Ongoing Phase ◽

Systemic Therapies

Abstract Introduction: Duvelisib (IPI-145) belongs to an emerging class of therapeutic small molecule kinase inhibitors that target B-cell receptor (BCR) signaling pathways important in various lymphoproliferative disorders. Duvelisib, a novel oral inhibitor of PI3K-δ,γ, has shown clinical activity across a range of hematologic malignancies in an ongoing Phase 1 study. Some patients (pts) treated with ibrutinib (IBR), a BCR inhibitor that targets Bruton’s tyrosine kinase (BTK), have had disease progression and various mechanisms of IBR resistance have been characterized. Since the mechanism of action of duvelisib differs from IBR, duvelisib was evaluated in a subset of pts previously treated with IBR enrolled in an ongoing Phase I study. Methods: The study was designed to evaluate the safety, maximum tolerated dose, pharmacokinetics, and activity of orally administered duvelisib twice daily in 28-day cycles. Pts with relapsed/refractory (R/R) hematologic malignancies were enrolled, including pts previously treated with IBR with R/R chronic lymphocytic leukemia (CLL) and aggressive B-cell NHL (aNHL including DLBCL and Richter’s transformation [RT]). Pharmacodynamic studies in CLL pts with measurable disease in the peripheral blood (PB) included flow cytometry to evaluate whether duvelisib inhibits the phosphorylation of AKT (pAKT) at S473 and the CLL cell proliferation index via measurement of Ki67. DNA sequencing on malignant PB cells was performed to determine the mutation status of BTK and other genes involved in hematologic malignancies. Clinical responses were based on IWCLL (2008) criteria and revised IWG (2007) criteria as applicable. Results: Twelve pts previously treated with IBR were enrolled (R/R CLL, n=6; aNHL, n=6 [DLBCL=2; RT=4]) and received IPI-145 at 25 mg BID (n=2) or 75 mg BID (n=10). The median age in R/R CLL pts was 58 years (y) (42-76), 67% were male, 100% had ≥3 prior systemic therapies, the median time from prior therapy to first dose of duvelisib was 0.34 months (mo) (0.0-1.6), and 67% started duvelisib within 2 wks of last dose of IBR. The median age in R/R aNHL pts was 62 y (36-81), 67% were male, 50% had ≥3 prior systemic therapies, a median time from last prior therapy to first dose of duvelisib of 0.74 months (0.2-3.7), and 50% started duvelisib within 3 weeks of last dose of IBR. With a median of 4.1 treatment cycles (range 3.0-9.2) in the R/R CLL pts and 2.5 treatment cycles (range 1.8-5.4) in R/R aNHL pts, the safety profile in these pts previously treated with IBR appears consistent with all pts (n=206) with advanced hematologic malignancies receiving duvelisib. The best response observed in R/R CLL pts includes 1 partial response (PR) and 5 stable disease (SD). Of these 6 pts, 2 pts (1 PR, 1 SD) remain on duvelisib for 8 and 9 months, respectively, and 4 pts have discontinued treatment (progressive disease [PD], n=3; physician decision, n=1). The best response observed in R/R aNHL pts included 2 PRs, 1 SD, 2 PD, and 1 not evaluated [NE]. Three pts remain on duvelisib (1 PR, 1 SD, 1 NE) for 3-5 mo and 3 pts have discontinued treatment (progressive disease, n=2; AE, n=1). The median baseline proliferative index (Ki67) in R/R CLL pts previously treated with IBR (n=5) was substantially higher (22.2% vs 3.8%) than in non-IBR exposed R/R CLL pts (n=23). Across both R/R CLL populations, Ki67 was reduced with duvelisib treatment by Cycle 2 Day 1 (at steady state); however, the effect was more pronounced in non-IBR treated pts. Despite this apparent difference in baseline proliferative index, the IBR previously treated pts with measureable disease in PB (R/R CLL=5), including 3 pts with a known IBR-resistance mutation in BTK (2 with C481S, 1 with C481F) demonstrated reductions of pAKT that were observed within 1 hour of duvelisib treatment and sustained through 24 hours postdose. This pAKT pharmacodynamic response was consistent with results in R/R CLL pts not previously treated with IBR (n=35). Conclusions: Pharmacodynamic data demonstrates duvelisib inhibits pAKT in R/R CLL pts, including those with an IBR-resistance mutation in BTK, and is consistent with duvelisib having a non-overlapping MOA with IBR. Baseline Ki67 data suggest a more aggressive clinical phenotype in R/R CLL pts who progress on IBR compared to those without previous IBR treatment. Early evidence of clinical activity and a tolerable safety profile suggest additional studies of duvelisib in pts who have progressed on IBR are warranted. Disclosures Porcu: Actelion (e), Cutaneous Lymphoma Foundation (h), United States Cutaneous Lymphoma Consortium (h), Infinity (d), Celgene (d), : Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: IPI-145. Flinn:Infinity Pharmaceuticals: Consultancy. Kahl:Infinity Pharmaceuticals: Consultancy, Research Funding. Horwitz:Research: Celgene, Millennium, Infinity, Kiowa-Kirin, Seattle Genetics, SpectrumConsulting: Amgen, Bristol-Myers Squibb, Celgene, Jannsen, Millennium, seattle genetics: Consultancy, Honoraria, Research Funding. Oki:Infinity Pharmaceuticals: Research Funding. Byrd:Pharmacyclics, Genentech: Research Funding. Sweeney:Infinity Pharmaceuticals: Employment. Allen:Infinity Pharmaceuticals: Employment. Faia:Infinity Pharmaceuticals, Inc.: Employment. Ni:Infinity Pharmaceuticals: Employment. Stern:Infinity Pharmaceuticals, Inc.: Employment. Kelly:Infinity Pharmaceuticals: Employment.

Download Full-text

A Phase I/II Trial of the KSP Inhibitor ARRY-520 In Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v116.21.1959.1959 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1959-1959 ◽

Cited By ~ 4

Author(s):

Jatin J Shah ◽

Jeffrey A. Zonder ◽

Adam Cohen ◽

Donna Weber ◽

Sheeba Thomas ◽

...

Keyword(s):

Multiple Myeloma ◽

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

Single Agent ◽

Clinical Activity ◽

Employment Equity ◽

Heavily Pretreated ◽

Equity Ownership ◽

Ksp Inhibitor

Abstract Abstract 1959 Background: Kinesin Spindle Protein (KSP) is required for cell cycle progression through mitosis. Inhibition of KSP induces mitotic arrest and cell death. ARRY-520 is a potent, selective KSP inhibitor. Cancers such as multiple myeloma (MM) which depend on the short-lived survival protein MCL-1 are highly sensitive to treatment with ARRY-520. ARRY-520 shows potent activity in preclinical MM models, providing a strong rationale for its clinical investigation in this disease. Methods: This Phase 1 study was designed to evaluate the safety and pharmacokinetics (PK) of ARRY-520 administered intravenously (IV) on Day 1 and Day 2 q 2 weeks without/with granulocyte-colony stimulating factor (G-CSF). Patients (pts) with relapsed/refractory (RR) MM with 2 prior lines of therapy (including both bortezomib and an immunomodulatory agent, unless ineligible for or refusing to receive this therapy) were eligible. Cohorts of at least 3 pts were enrolled in a classical 3 + 3 dose escalation design. Pts were treated for 2 cycles (4 weeks) to evaluate safety prior to dose escalation. Results: Twenty five pts have been treated to date, with a median age of 60 years (range 44–79) and a median of 5 prior regimens (range 2–16). All pts received prior bortezomib or carfilzomib, 21 pts received prior lenalidomide, 17 pts prior thalidomide, and 18 pts had a prior stem cell transplant. Pts received ARRY-520 without G-CSF at 1 mg/m2/day (n = 3), and at 1.25 mg/m2/day (n = 7, 6 evaluable). A dose-limiting toxicity (DLT) of Grade 4 neutropenia was observed at 1.25 mg/m2/day, and this was considered the maximum tolerated dose (MTD) without G-CSF. As neutropenia was the DLT, dose escalation with prophylactic G-CSF support was initiated, at doses of 1.5 mg/m2/day (n = 7, 6 evaluable), 2.0 mg/m2/day (n = 6) and 2.25 mg/m2/day (n = 2) with G-CSF. Both the 2.0 mg/m2/day and 2.25 mg/m2/day dose levels were determined to be non-tolerated, with DLTs of febrile neutropenia (FN) (2 pts at 2.0 mg/m2/day and both pts at 2.25 mg/m2/day) and Grade 3 mucositis (both pts at 2.25 mg/m2/day). One out of 6 evaluable pts at 1.5 mg/m2/day also developed a DLT of FN. In an attempt to optimize the Phase 2 dose, an intermediate dose level of 1.75 mg/m2/day with G-CSF is currently being evaluated. The most commonly reported treatment-related adverse events (AEs) include those observed with other KSP inhibitors, such as hematological AEs (thrombocytopenia, neutropenia, anemia, leukopenia), fatigue, mucositis and other gastro-intestinal AEs. Pts displayed linear PK, a low clearance and a moderate volume of distribution, with moderate-to-high inter-individual variability in PK parameters. The median terminal elimination half life is 65 hours. The preliminary efficacy signal as a single agent is encouraging with 2 partial responses (PR) observed to date per IMWG and EBMT criteria in a heavily pretreated population (23 evaluable pts). A bortezomib-refractory pt with 8 prior lines of therapy, including a tandem transplant, treated at 1 mg/m2/day of ARRY-520 obtained a PR after Cycle 6, with urine protein and kappa light chain levels continuing to decline over time. He remains on-study after 15 months of ARRY-520 treatment. A pt with 2 prior lines of therapy, including prior carfilzomib, has obtained a PR after Cycle 8 at 2 mg/m2/day of ARRY-520, and she is currently ongoing after 4.5 months on therapy. Fifteen pts had a best response of stable disease (SD), including 1 pt with a thus far unconfirmed minimal response, and 6 had progressive disease. A total of 10 pts (43%) achieved a PR or SD lasting > 12 weeks. Several additional pts have shown other evidence of clinical activity, with decrease in paraproteins, increase in hemoglobin levels and regression of plasmacytomas. The median number of cycles is 4 (range 1–28+). Treatment activity has not correlated with any baseline characteristics or disease parameters to date. Conclusions: : The selective KSP inhibitor ARRY-520 has been well tolerated, and shows promising signs of single agent clinical activity in heavily pretreated pts with RR MM. Prophylactic G-CSF has enabled higher doses to be tolerated. No cardiovascular or liver enzyme toxicity has been reported. Enrollment is ongoing at 1.75 mg/m2/day with G-CSF support, and a planned Phase 2 part of the study will be initiated as soon as the MTD is determined. Complete Phase 1 data will be disclosed at the time of the meeting. Disclosures: Shah: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding. Off Label Use: Revlimid (lenalidomide) in combination with dexamethasone is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy. Zonder:Millennium: Consultancy, Myeloma and Amyloidosis Patient Day Symposium – Corporate support from multiple sponsors for a one-day educational event, Research Funding; Celgene:; Novartis:; Proteolix: . Weber:novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; celgene- none for at least 2 years: Honoraria; millenium-none for 2 years: Honoraria; celgene, Millenium, Merck: Research Funding. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Kaufman:Celgene: Consultancy, Honoraria, Research Funding; Millenium: Consultancy, Honoraria; Merck: Research Funding; Genzyme: Consultancy. Walker:Array Biopharma: Employment, Equity Ownership. Freeman:Array Biopharma: Employment, Equity Ownership. Rush:Array Biopharma: Employment, Equity Ownership. Ptaszynski:Array Biopharma: Consultancy. Lonial:Millennium, Celgene, Bristol-Myers Squibb, Novartis, Onyx: Advisory Board, Consultancy; Millennium, Celgene, Novartis, Onyx, Bristol-Myers Squibb: Research Funding.

Download Full-text

Lenalidomide (Revlimid), Bortezomib (Velcade) and Dexamethasone (RVD) for Heavily Pretreated Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v118.21.2936.2936 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2936-2936

Author(s):

Victor H Jimenez-Zepeda ◽

Donna E. Reece ◽

Suzanne Trudel ◽

Christine Chen ◽

Vishal Kukreti

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Research Funding ◽

Clinical Characteristics ◽

Phase 1 ◽

Prior Exposure ◽

Rank Test ◽

Continuous Variables ◽

Previously Treated ◽

Grade 3

Abstract Abstract 2936 Almost all patients (pts) with multiple myeloma eventually relapse and remission duration decreases with each regimen. The median Progression Free Survival (PFS) and Overall Survival (OS) in pts with relapsed myeloma refractory to lenalidomide (len) and bortezomib (btz) is poor at 5 and 9 months respectively. A phase 1 study of len plus btz in pts with relapsed or relapsed, refractory MM (RRMM) demonstrated favorable toxicity and promising response and survival further confirmed in a phase 2 study with len, btz and dexamethasone (dex) [RVD]. In this retrospective study, we assessed the efficacy and toxicity profile of RVD therapy for pts with advanced RRMM. We retrospectively reviewed the records of all pts with RRMM treated with RVD at Princess Margaret Hospital between 03/09 and 05/11. Relapse was defined according to the Uniform International Criteria. Pts were given RVD therapy as previous described by Anderson et al and must have completed at least one cycle of RVD therapy. Primary endpoints were response rate (RR), PFS, OS, and toxicity. Pts discontinued therapy if they experienced PD, no additional benefit or unacceptable toxicity. Definitions of response and progression were used according to the EBMT modified criteria with a category of very good partial response (VGPR). To examine variables independently prognostic for PFS and OS, multivariate Cox analysis was performed. Differences in continuous variables between groups were compared using Mann-Whitney or Kruskal-Wallis tests. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test. Thirty pts with RRMM received RVD therapy. Clinical characteristics are seen in Table 1. Median age at RVD initiation was 57 yrs (37–76 yrs), and 46.7% were male. Pts received a median of 3 prior therapies (1–6). In many instances, pts previously treated with len had len added to btz + dex at progression (n=6), or pts previously treated with btz had btz added to len + dex, at progression (n=5). Thalidomide (thal), len and btz containing regimens were previously used in 60%, 73.3% and 80% of pts respectively. PR or better was observed in 46.6%. After a median of 4.6 cycles (1–14), VGPR was seen in 4.8%, PR in 33% and SD in 14%. Pts who achieved PR or better experienced a significant improvement in PFS. There was no difference in terms of RR between those pts according to prior exposure to either btz or len (p=0.7 and 0.9 respectively). Eight pts experienced non-hematological grade 3/4 adverse events (26%), including muscle weakness, sepsis and pneumonia but there was no worsening of peripheral neuropathy. Grade 3–4 neutropenia and/or thrombocytopenia were commonly seen in 70% of pts (n=21). Disease progression was seen in 19 pts at a median of 3.9 months. Median PFS for pts previously exposed to len was 2.3 months vs 2.9 months for those with no prior exposure (p=0.75). On the other hand, median PFS for pts previously exposed to btz was 2.1 months vs 3.4 months for those with no prior exposure (p=0.9) In addition, median PFS for pts who achieved at least PR was significantly better at 5.9 vs 2.0 months for those who did not (p<0.005). (Figure 1) FISH cytogenetics studies were available in 19 out of 30 patients at relapse: 5 -normal, 4–13q deletion, 3-p53 deletion and 2 - t(4, 14). High-risk MM pts had a median PFS significantly lower of 0.6 months (CI 95%, 0–1.99) vs 4.7 months for those without high-risk features (CI 2.5–7.0) (p=0.008) (Figure 2) At the time of submission, 13 pts are alive (43.3%) and 7 pts (23%) continue on RVD therapy.Table 1.Clinical characteristics of patients with RRMM treated with RVDClinical characteristic N=30MedianRange%Age5737-76Male46.7%Female53.3%Hemoglobin (g/L)10571-155Creatinine (mmol/L)99.936-383Beta-2 microglobulin (mmol/L)280119-1440Lactate dehydrogenase (U/L)18189-255IgG56.6% (17)IgA23.3% (7)IgM3.3% (1)Light Chain16.6% (5)Kappa (mg/L)4005.3-346063.3% (19)Lambda (mg/L)5145.1-530036.7% (11)KappaLambda*BMPC57%6-95%M-spike serum (g/L)300-77M-spike urine (g/d)0.890-7.9Prior therapies31-6ASCT83.3% (25)Thal60% (18)Len73.3% (22)Btz80% (24)*BMPC, Bone marrow plasma cells In conclusion, RVD is active and well tolerated in pts with RRMM, including pts who have received prior len, btz, thal and ASCT but PFS is short at 3.9 months in this highly advanced disease group of patients. We question whether response is dependent on recognized risk factors such as adverse cytogenetics. Disclosures: Jimenez-Zepeda: J & J: Honoraria. Reece:Bristol, Meyers, Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Johnson&Johnson: Research Funding; Merck: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Millennium: Research Funding; Amgen: Honoraria. Kukreti:Celgene: Honoraria.

Download Full-text

Identification of Alpha 1-Acid Glycoprotein (AAG) As a Potential Patient Selection Biomarker for Improved Clinical Activity of the Novel KSP Inhibitor ARRY-520 in Relapsed and Refractory Multiple Myeloma (MM)

Blood ◽

10.1182/blood.v120.21.1868.1868 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1868-1868 ◽

Cited By ~ 4

Author(s):

Brian Tunquist ◽

Karin Brown ◽

Gary Hingorani ◽

Sagar Lonial ◽

Jonathan L. Kaufman ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Phase 1 ◽

Clinical Activity ◽

Advisory Committees ◽

Blood Samples ◽

Refractory Multiple Myeloma

Abstract Abstract 1868 Background ARRY-520 is a kinesin spindle protein (KSP) inhibitor that has demonstrated clinical activity in patients with relapsed and refractory multiple myeloma (MM). Although ARRY-520 is administered IV, it displays variable pharmacokinetics (PK) among patients. The degree of binding of certain drugs to serum proteins can alter their free fraction (fu) and PK, with a possible impact on clinical activity. Alpha 1-acid glycoprotein (AAG) is an acute-phase reactant protein that is often elevated in the blood of patients with cancer, including multiple myeloma. We investigated the significance of the interaction of ARRY-520 with AAG, and other relevant blood proteins, using both in vitro models and clinical data. Methods Compound-protein binding was assessed using several in vitro assays. In addition, the effect of increasing concentrations of AAG on MM cell line viability was measured. Patient data were obtained from 3 clinical studies of ARRY-520: a Phase 1 solid tumor study, a Phase 1/2 AML study, and a Phase 1/2 study in MM. The MM Phase 2 portion consists of 2 separate, 2-stage cohorts. Cohort 1 evaluated ARRY-520 administered as a single agent, and cohort 2 investigated ARRY-520 in combination with low-dose dexamethasone (LoDex). The concentrations of multiple proteins, including AAG, and the degree of ARRY-520 total protein binding, were measured in pre- and post-dose blood samples for patients in the analysis. AAG levels in MM patients were further correlated with time-on-study and clinical response rate. Results ARRY-520 exhibits low micromolar affinity for AAG in in vitro assays, but not for other common serum proteins, such as albumin. To investigate whether AAG binding impacts biological activity, we found that increasing AAG concentrations within a clinically relevant range resulted in increasing IC50 values for ARRY-520 on MM cell line viability. Of other MM agents tested, none exhibited high affinity binding to AAG in vitro, and a range of AAG concentrations did not alter the cellular activity of these compounds. Pre-dose concentrations of AAG were measured using blood samples collected from patients on all 3 ARRY-520 studies (0.4 – 4.1 g/L AAG in solid tumor study; 0.5 – 2.4 g/L in AML study; 0.2 – 2.8 g/L in MM study). Post-dose blood samples from the MM study also indicated that AAG levels do not significantly change with time. The fu of ARRY-520 in blood was meaningfully reduced among patients with the highest AAG concentrations. Furthermore, AAG and fu were correlated with changes in clinical PK: CL and Vd decreased with increasing AAG, trends consistent with a lower fu. Among the MM patients, 72 patients were evaluable for AAG determination (27 from the dose-escalation portion, 27 from Cohort 1, and 18 from Stage 1 of Cohort 2). Across all of these cohorts, the group of patients with AAG above an empirically-determined cutoff of 1.1 g/L showed a decreased median time on study (1.5 months vs 4.7 months) and no clinical responses (0/19 vs 12/53) as compared to patients below this cutoff. For example, as reported separately, ARRY-520 in combination with LoDex showed a promising 22% overall response rate (≥PR) in the 1st-stage of Cohort 2. In this cohort, 6 patients were determined to have AAG concentrations above the empirical cutoff. None of these patients had clinical benefit. Excluding these 6 patients would significantly improve the overall response rate (≥PR) from 22% (4/18) to 33% (4/12). Summary AAG has been proposed as a prognostic marker for MM disease severitya. Our preliminary data suggest that AAG levels can affect the free fraction of ARRY-520 in blood over a clinically relevant range both preclinically and in clinical studies. In retrospective analysis, patients with higher AAG levels show a lower fu and therefore may not achieve sufficient exposure to gain therapeutic benefit from ARRY-520. In preclinical analyses, this effect is specific to ARRY-520, suggesting that AAG levels may be predictive for ARRY-520 activity relative to other MM drugs. We hypothesize that prospective screening for AAG may enable exclusion of patients who may not achieve therapeutic exposure to ARRY-520, increasing the overall activity of ARRY-520 and preventing exposure of non-responders to an ineffective therapeutic dose. Further, experiments are currently underway to investigate the relevance of other acute-phase proteins in blood. Disclosures: Tunquist: Array BioPharma: Employment. Off Label Use: ARRY-520 alone and with dexamethasone for the treatment of relapsed/refractory multiple myeloma. ARRY-520 is not currently approved for any indication. Brown:Array BioPharma: Employment. Hingorani:Array BioPharma: Employment. Lonial:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kaufman:Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy. Zonder:Celgene: Honoraria, Research Funding; Millenium: Honoraria, Research Funding. Orlowski:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Shah:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Hilder:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Consultancy. Koch:Array BioPharma: Employment. Litwiler:Array BioPharma: Employment. Walker:Array BioPharma: Employment.

Download Full-text

Phase 1 Study of Tabalumab, a Human Anti-BAFF Antibody and Bortezomib in Patients with Previously-Treated Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.447.447 ◽

2012 ◽

Vol 120 (21) ◽

pp. 447-447 ◽

Cited By ~ 6

Author(s):

Noopur Raje ◽

Edward Anthony Faber ◽

Paul G. Richardson ◽

Gary J. Schiller ◽

Raymond J. Hohl ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Median Number ◽

Phase 1 Study ◽

Advisory Committees ◽

Baseline Serum ◽

Lower Baseline ◽

Previously Treated

Abstract Abstract 447 Background: Tabalumab, a human mAb that neutralizes membrane-bound and soluble B cell activating factor (BAFF), has demonstrated both anti-myeloma activity and osteoclastogenesis inhibition in xenograft models of multiple myeloma (MM). We initially conducted a Phase 1 study with the combination of tabalumab and bortezomib in previously-treated MM patients who were not refractory to bortezomib. The results from the dose escalation (Part A) have been previously reported, where a tabalumab dose of 100 mg was selected based on several factors, most notably the stabilization of the peak to trough concentration ratio. The cohort expansion (Part B) has since completed enrollment, and we now report the preliminary results for the entire study. Methods: The primary objective was to identify a safe and potentially efficacious dose of tabalumab to be combined with bortezomib. Bortezomib was given in a standard biweekly fashion, 1.3 mg/m2 IV on days 1, 4, 8, and 11 of a 21 day cycle, and tabalumab at 1, 10, 30, 100, or 300 mg (Part A) or 100 mg (Part B) IV (30 min) on day 1 in Cycles 1 – 3, 5, and 7. The study was later amended to include dexamethasone to assess safety, and 12 patients received dexamethasone in combination with bortezomib and tabalumab. Response was assessed per IMWG criteria and adverse events per CTCAE v3.0. Pharmacokinetic (PK) and pharmacodynamic (PD) samples were obtained throughout the study, including BAFF, IL-1beta, IL-6, IL-10, VEGF, and TNF-alpha. Results: Forty-eight patients were enrolled to the study; 20 to dose escalation (Part A) and 28 to cohort expansion (Part B). The median age was 65.7 years and 56% were women. The median number of prior therapies was 3 (range 1–10). All patients received either bortezomib or an IMiD; 75% received prior bortezomib and 88% received prior IMiD therapy. The median number of cycles was 5.5 (range 1–28). Grade 3/4 toxicities occurring in two or more patients included peripheral sensory neuropathy, pneumonia, thrombocytopenia, neutropenia, diarrhea, musculoskeletal pain, renal failure acute, fatigue, anemia, neuralgia, and gastrointestinal hemorrhage. Most patients discontinued treatment due to progressive disease or adverse events (neuropathy, neuralgia, fatigue, and thrombocytopenia). Two patients died during study participation - one during treatment from acute respiratory distress syndrome and another during follow-up from multiple myeloma. Confirmed responses included 2 complete responses, 4 very good partial responses, and 16 partial responses. Response associated with lower baseline serum BAFF or IL-6 levels, independent of the tabalumab dose. Also, response in patients treated with tabalumab 100 mg appeared to associate with lower baseline serum levels of IL-10 and undetectable TNF-alpha. With 14 patients censored, the TTP was 4.9 months (95% CI: 4 – 8). With 6 patients censored, the median response duration was 7.3 months (95% CI: 3.5 – 13.9). Conclusions: A 100 mg dose of tabalumab in combination with bortezomib was well tolerated; 22 patients achieved a PR or better despite prior bortezomib and/or IMiD therapy. Response correlated with lower baseline serum BAFF levels, supporting the hypothesis that a higher dose of tabalumab should be evaluated. A three-arm study randomizing patients to the combination(s) of bortezomib, dexamethasone, and tabalumab 100 mg vs. tabalumab 300mg vs. placebo is currently enrolling. Disclosures: Raje: Onyx: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Acetylon: Research Funding; Amgen: Research Funding; Eli-Lilly: Research Funding. Richardson:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Schiller:Eli Lilly & Company: Research Funding. Cohen:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Carpenter:Eli Lilly & Company: Employment. Cronier:Eli Lilly and Company: Employment. Kaiser:Eli Lilly and Company: Employment. Wooldridge:Eli Lilly and Company: Employment. Anderson:Acetylon, Oncopep: Scientific Founder, Scientific Founder Other; Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

An Open-Label, Dose Escalation, Multi-Center Phase 1 Study of PRLX 93936, an Agent Synthetically Active Against the Activated Ras Pathway, in the Treatment of Relapsed or Relapsed and Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.2140.2140 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2140-2140 ◽

Cited By ~ 2

Author(s):

Peter M Voorhees ◽

Robert L. Schlossman ◽

Cristina J Gasparetto ◽

Jesus G. Berdeja ◽

John Morris ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Progressive Disease ◽

Phase 1 ◽

Single Agent ◽

Open Label ◽

Advisory Committees ◽

Ras Pathway ◽

Label Dose

Abstract Introduction: Overall survival for patients with multiple myeloma (MM) has improved, but most patients relapse and eventually succumb to complications of the disease. The development of new therapeutic agents to treat relapsed and relapsed/refractory MM is therefore vital. Proteins of the Ras family are frequently mutated in human cancers, including MM. However, direct, selective, potent inhibitors of mutant Ras proteins are not clinically available. Extensive efforts have been made to identify agents which are "synthetically active" against the activated Ras pathway which may not inhibit the Ras protein itself, but target other molecules selectively important for cells with, but not those without, Ras mutation. PRLX 93936, 3-(2-ethoxyphenyl)-2-[(1-piperazinyl)methyl]-4(3H)-quinazolinone, is an analog of such a "synthetically active" compound against the activated Ras pathway. The compound has demonstrated promising efficacy in preclinical laboratory studies and mouse models of MM with an improvement in survival and 30% suppression in tumor growth at the lowest tested dose. A phase 1, multi-center, open-label, dose escalation trial was conducted to determine the maximum tolerated dose (MTD), assess toxicities, and evaluate response to treatment with monotherapy of PRLX 93936 in patients with relapsed or relapsed/refractory MM. Methods: Patients (Pts) with relapsed or relapsed/refractory MM in whom at least two prior anti-myeloma regimens had failed (including a proteasome inhibitor and/or immunomodulatory drug) were considered. PRLX 93936 as a single agent was given intravenously 3 days/week for 3 weeks followed by a 9 day rest period constituting a 28-day treatment cycle. Sequential cohorts of at least three pts were treated with escalating doses of PRLX 93936 beginning at 10 mg/m2 and increasing the dose in increments of 5mg/m2 until the MTD was established. Pts received a minimum of 2 cycles of treatment at their assigned dose level for evaluation of anti-myeloma activity of PRLX 93936 and could receive up to 8 cycles followed by an option of maintenance therapy. Dexamethasone at a dose of 20 mg provided on each day of PRLX 93936 infusion could be added at the investigator’s discretion after a minimum of 2 cycles or after cycle 1 for patients with progressive disease. Adverse events were assessed according to version 4.0 of the CTC, and response per the International Myeloma Working Group uniform response criteria, incorporating the modified EBMT response criteria, were assessed with each cycle. Correlative studies from peripheral blood and bone marrow were collected. Results: To date, 14 pts (4 women, 10 men) enrolled in the trial and 13 have completed therapy. Mean age was 61 years (range, 48-81). Prior to enrollment, pts had received an average of 5 lines of therapy (median 4, range 2-9) including 6 who received stem cell transplantation (4 autologous, 2 allogeneic). The median time since diagnosis was 5 years (range 2-11.5). Of the 13 pts whom completed treatment, 11 completed at least one full 28 day cycle (range 1-15). This includes 3 pts at the 10mg/m2 dose, 3 pts at the 15mg/m2 dose, 5 pts at the 20 mg/m2 dose, and 2 pts at the 25mg/m2 dose. Of the 13 pts who completed study therapy, 7 experienced at least one serious adverse event (SAE). The most frequently reported SAEs (2 each) included sepsis and cellulitis. Four SAEs were considered related to PRLX 93936 by the investigator (thrombocytopenia, neutropenia, nausea, and vomiting). The MTD was determined to be 20 mg/m2. Dose limiting toxicities that occurred at the next higher level of 25mg/m2 included nausea, vomiting, and neutropenia (both pts) and thrombocytopenia, weakness, elevated AST, and elevated creatinine (1 pt). The best response among 11 evaluable pts was minimal response (MR) in 2 pts (18%). Stable disease (n=4) and progressive disease (n=5) was observed in the remaining pts. Analysis of the impact of dexamethasone is on-going, but no significant additive toxicity has been seen. Conclusions: PRLX 93936, a “synthetically active” compound against the activated Ras pathway, has demonstrated activity as a single agent in relapsed and refractory MM patients with MR in 18% of patients to date. Toxicity has proven manageable and the MTD has been defined at 20 mg/m2. Additional studies, including those involving PRLX 93936 as part of combination therapy and correlative studies to determine those pts most likely to benefit, are warranted. Disclosures Voorhees: Millennium: The Takeda Oncology Company : Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees. Off Label Use: PRLX 93936 is a non-FDA approved drug currently in phase 1 development in multiple myeloma. Gasparetto:Millenium: Honoraria; Celgene: Consultancy, Honoraria. Jacobstein:Prolexys Pharmaceuticals, Inc: Employment. Anderson:BMS: Consultancy; Sanofi Aventis: Consultancy; Gilead: Consultancy; Onyx: Consultancy; Millenium: Consultancy; Celgene: Consultancy; Oncopep/Acetylon: Equity Ownership. Mitsiades:Millennium: A Takeda Oncology Company: Consultancy; Celgene: Consultancy; Johnson & Johnson: Research Funding; Amgen: Research Funding. Laubach:Celgene: Research Funding; Novartis: Research Funding; Millennium: A Takeda Oncology Company: Research Funding; Onyx: Research Funding. Richardson:Janssen: Membership on an entity's Board of Directors or advisory committees; Millennium: The Takeda Oncology Co.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Phase 1 Study of the Investigational Proteasome Inhibitor Ixazomib Alone or in Combination with Lenalidomide–Dexamethasone (Rd) in Japanese Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM)

Blood ◽

10.1182/blood.v124.21.5752.5752 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5752-5752 ◽

Cited By ~ 2

Author(s):

Hiroshi Handa ◽

Kenshi Suzuki ◽

Takaaki Chou ◽

Takafumi Matsushima

Keyword(s):

Multiple Myeloma ◽

Proteasome Inhibitor ◽

Research Funding ◽

Phase 1 ◽

Single Agent ◽

Japanese Patients ◽

M Protein ◽

Phase 3 ◽

Grade 3 ◽

Ongoing Phase

Background Ixazomib is the first oral proteasome inhibitor to be investigated clinically for the treatment of MM. Phase 1 studies have shown single-agent activity and manageable toxicities in RRMM (Kumar et al. Blood 2014) and phase 1/2 studies have suggested the feasibility and activity of weekly oral ixazomib plus Rd in previously untreated MM (Kumar et al. ASH 2012; Richardson et al. ASH 2013). These findings have led to ongoing phase 3 trials of weekly ixazomib 4 mg + Rd in RRMM and previously untreated MM. However, the early-phase studies were conducted in Western pts. This phase 1, open-label multicenter study aimed to determine the safety, tolerability, and pharmacokinetics (PK) of weekly ixazomib alone or with Rd in Japanese pts with RRMM (Japic Clinical Trials Information no. 121822). Methods Primary objectives were to evaluate the safety and tolerability, including dose-limiting toxicities (DLTs) and adverse events (AEs), and the PK of ixazomib alone or with Rd. A secondary objective was evaluation of antitumor activity. Japanese pts aged ≥20 years with RRMM who had received at least 2 prior regimens, which must have included bortezomib, thalidomide or lenalidomide, and corticosteroids, were eligible. All had measurable disease and ECOG performance status of 0–2. Pts with grade ≥2 peripheral neuropathy or grade ≥2 diarrhea at study entry were excluded. Pts received ixazomib 4 mg on days 1, 8, and 15 of 28-day cycles, alone or with Rd (lenalidomide 25 mg on days 1–21, dexamethasone 40 mg on days 1, 8, 15, and 22), per the regimen used in the ongoing phase 3 trials. AEs were graded per NCI-CTCAE v4.03. Blood samples for PK analysis were taken at multiple time points prior to and after dosing on days 1 and 15 of cycle 1. Responses were assessed per IMWG uniform response criteria. Results Fourteen pts were enrolled; 8 (57%) were male, median age was 62.5 yrs (range 53–71), 4 pts were aged ≥65 yrs, median number of prior therapies was 7. Seven pts received single-agent ixazomib and 7 received ixazomib + Rd. One pt in each cohort was excluded from the DLT-evaluable population. Two patients experienced DLTs in cycle 1: 1 pt receiving single-agent ixazomib had grade 4 thrombocytopenia and grade 3 diarrhea, hypertension, hypokalemia, hyponatremia, and nausea; 1 pt in the ixazomib + Rd cohort had grade 4 thrombocytopenia and neutropenia. All events were considered treatment-related. At data cut-off (Jan 6 2014), 6 pts remained on treatment and 8 had discontinued due to: progressive disease (PD; n=3), AEs (n=3), symptomatic deterioration, and protocol violation (each n=1). At data cut-off, pts (n=14) had received a median of 6 cycles of ixazomib (range 1–21); the 7 pts in the ixazomib + Rd cohort had received a median of 4 cycles (range 1–12) of ixazomib + Rd. Thirteen (93%) pts experienced treatment-related AEs; the most common were neutropenia (71%), thrombocytopenia (71%), leukopenia (64%), lymphopenia (57%), and diarrhea (50%). There were no cases of peripheral neuropathy. Nine (64%) pts had grade ≥3 AEs; the most common were lymphopenia (50%), neutropenia (43%), and thrombocytopenia (36%). Two (14%) pts (single-agent cohort) had serious AEs (grade 2 bronchitis in 1 pt, and grade 4 thrombocytopenia and grade 3 hypokalemia in 1 pt). Three pts discontinued due to AEs; 1 due to diarrhea in the single-agent cohort, and 1 due to neutropenia and 1 due to thrombocytopenia in the ixazomib + Rd cohort. There were no deaths. PK data showed ixazomib was rapidly absorbed with a Tmax at 1.08–1.83 hrs. Terminal half-life (geometric mean) was 5.7 days for single-agent ixazomib and 5.2 days for ixazomib + Rd. There were no substantial differences in the ixazomib PK profile between the two cohorts. Thirteen pts were response-evaluable. One pt (ixazomib + Rd cohort) had a partial response; at data cut-off, this pt remained in response with a 100% M-protein reduction (unconfirmed VGPR) and duration of response of ~10.8 months. Seven pts had stable disease (including 3 with M-protein reductions of 25–50%), 2 had PD, and 3 were not assessable. Conclusions These data suggest that ixazomib 4 mg alone or with Rd is feasible and tolerable in Japanese pts with RRMM. The AEs were manageable, reflecting the AE profile seen in Western populations, supporting the use of this dose and schedule in Japanese pts. Disclosures Handa: Celgene: Research Funding; Yakult: Research Funding; Kirin: Research Funding; Chugai: Research Funding. Off Label Use: Investigational agent ixazomib for the treatment of Japanese patients with relapsed and/or refractory multiple myeloma.. Matsushima:Takeda Pharmaceutical Company Limited : Employment.

Download Full-text

A Phase 1/2, Dose and Schedule Evaluation Study to Investigate the Safety and Clinical Activity of Belantamab Mafodotin Administered in Combination with Lenalidomide and Dexamethasone in Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2021-152241 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2736-2736

Author(s):

Evangelos Terpos ◽

Maria Gavriatopoulou ◽

Ioannis Ntanasis-Stathopoulos ◽

Panagiotis Malandrakis ◽

Despina Fotiou ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Event ◽

Research Funding ◽

Phase 1 ◽

Safety Analysis ◽

Health Data ◽

Clinical Activity ◽

Newly Diagnosed ◽

Treatment Naïve ◽

Grade 3

Abstract Background: The combination of lenalidomide with dexamethasone (Rd) represents a preferred treatment backbone for newly diagnosed, transplant-ineligible patients (pts) with multiple myeloma (MM), while the addition of a third drug (i.e., daratumumab, bortezomib, carfilzomib or ixazomib) leads to higher response rates and deeper responses. Belantamab mafodotin (belamaf; GSK2857916) is a multi-modal antibody-drug conjugate that has demonstrated a clinically meaningful anti-myeloma activity with a manageable safety profile in heavily pre-treated pts with relapsed or refractory MM. Preclinical evidence suggest a potential synergy between belamaf and lenalidomide; at the same time, these drugs do not have overlapping toxicities. Thus, there is strong rationale for investigating the clinical activity of upfront belamaf in combination with Rd in transplant-ineligible MM pts. Aims: The present analysis evaluates the safety profile of belamaf in 3 different dosing schemes in combination with Rd in treatment-naïve, transplant-ineligible MM pts. Methods: BelaRd (study short title) is an open-label, single-center, phase 1/2 study conducted in Greece, aiming to enroll 66 newly diagnosed, transplant-ineligible MM pts. The study comprises 2 parts. Part 1 will evaluate 3 doses of belamaf (2.5, 1.9, and 1.4 mg/kg) in combination with Rd, each given in an individual cohort of pts, and will determine the recommended phase 2 dose (RP2D). In this part, belamaf will be administered q8w and, depending on toxicity, dosing may be rescheduled to q4w or q12w. In Part 2, a single cohort of pts will be treated with belamaf in the RP2D in combination with Rd to further evaluate the safety and clinical activity of this regimen. Part 2 will also evaluate 2 different sets of guidelines for ocular adverse events (AEs) in 2 separate groups of pts to identify the optimal method for the management of belamaf-related keratopathy. This is the initial safety analysis of Part 1 and includes pts who received ≥1 belamaf dose and were followed up for ≥8 weeks. Results: Overall, as of 16 July 2021 (cut-off date), 18 pts completed the dose-limiting toxicity (DLT) observation period, defined as specific ≥ grade 3 AEs occurring during the first cycle of study treatment, and were included in the safety analysis. The median age was 72 years (range: 65-82), and the majority of pts were male (55.6%). Lytic bone lesions were present in 12 (66.7%) pts; no pts had extramedullary disease. Most pts (9, 50.0%) had Eastern Cooperative Oncology Group performance status 0 followed by those at 1 (8, 44.4%) and 2 (1, 5.6%). Regarding the revised International Staging System, most pts (13, 72.2%) were at stage II, followed by those at stages III (2, 11.1%) and I (3, 16.7%); 3 (16.7%) pts had high-risk cytogenetics, defined as del17p13, t(4;14) or t(14;16). By the cut-off date, pts had received a median of 4 treatment cycles, with 17 (94.4%) pts still being on treatment; 1 (5.6%) pt died due to pneumonia, unrelated to the study treatment. 16 (88.9%) pts experienced ≥1 treatment emergent adverse event (TEAE). In total, 11 (61.1%) pts had ≥1 TEAE grade 3/4, of which 1 was related to belamaf; 1 (5.6%) pt experienced a serious adverse event (SAE). There were 2 cases of dose reduction and 1 case of dose delay. The most common grade 3/4 TEAEs were fatigue (5 pts, 27.8%) and rash (4 pts, 22.7%), all related to lenalidomide. One SAE was reported: pneumonia grade 5 in the 2.5 mg/kg cohort. DLTs were noted in 3 (16.7%) pts: 1 pt with grade 3 fatigue in the 1.4 mg/kg cohort and 1 pt with grade 3 rash in each of the 1.9 and 1.4 mg/kg cohorts, all related to lenalidomide. Regarding belamaf-related ocular AEs, there were 2 cases of superficial punctuate keratopathy (grade 1 and 2 each, both in the 2.5 mg/kg cohort), 10 cases of decreased visual acuity (grade 1 [8 pts, 44.4%]: 4 in the 1.9 mg/kg cohort and 4 in the 1.4 mg/kg cohort; grade 2 [2 pts, 11.1%] in the 2.5 mg/kg cohort), and 1 case of grade 1 blurred vision in 2.5 mg/kg cohort. Conclusions: In the first safety analysis of the BelaRd study no new safety signals for the belamaf-Rd combination were observed. The frequency of ocular AEs was within the anticipated range. This early analysis shows that the triplet combination can be safely administered in treatment-naïve, transplant-ineligible MM pts. The enrollment in the study is ongoing, and more safety and efficacy data will become available with the inclusion of additional pts in an updated analysis. Disclosures Terpos: Novartis: Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Honoraria. Gavriatopoulou: Janssen: Honoraria; Takeda: Honoraria; Karyopharm: Honoraria; GSK: Honoraria; Genesis: Honoraria; Sanofi: Honoraria; Amgen: Honoraria. Gkolfinopoulos: Health Data Specialists: Current Employment. Manousou: Health Data Specialists: Current Employment. Dimopoulos: Janssen: Honoraria; Beigene: Honoraria; Takeda: Honoraria; BMS: Honoraria; Amgen: Honoraria.

Download Full-text

Final Results of a Phase 1/2 Open-Label Study to Assess the Safety, Tolerability and Preliminary Efficacy of Evofosfamide, a Hypoxia-Activated Prodrug, and Dexamethasone with or without Bortezomib in Subjects with Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.2122.2122 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2122-2122

Author(s):

Jacob P. Laubach ◽

Noopur Raje ◽

Andrew J. Yee ◽

Philippe Armand ◽

Robert L. Schlossman ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Stable Disease ◽

Research Funding ◽

Phase 1 ◽

Median Number ◽

Clinical Activity ◽

Advisory Committees ◽

Refractory Multiple Myeloma ◽

Grade 3

Abstract Purpose: This phase 1/2 study was conducted to determine the maximum tolerated dose (MTD), safety, tolerability, and clinical activity of the hypoxia-activated prodrug evofosfamide (TH-302) and dexamethasone with or without bortezomib in relapsed/refractory multiple myeloma. Patients & Methods: Patients were enrolled to stage A (evofosfamide + dexamethasone) followed by stage B (evofosfamide + bortezomib + dexamethasone). Stage A enrollment began in March 2012 and ended in May 2014. In total 34 patients were enrolled to stage A, with 31 patients being treated. Stage B enrollment began in June 2014 and ended in July 2015. In total 28 patients were enrolled and treated on stage B. Patients enrolled on study were diagnosed with relapsed/ refractory multiple myeloma (RRMM), had adequate hepatic, renal, and hematologic function, as well as an ECOG performance status of ≤2, and had all received at least 2 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. In stage B, patients previously receiving bortezomib must not have discontinued due to toxicity. Patients must have had measureable disease as determined by the International Working Group (IMWG) criteria. In stage A, evofosfamide was administered IV in conjunction with a fixed oral dose of 40 mg dexamethasone on Days 1, 4, 8 and 11 of a 21-day cycle. In stage B, evofosfamide was administered in conjunction with a fixed oral dose of 40 mg dexamethasone and a fixed IV or SC dose of 1.3 mg/m2 bortezomib. Stage A dose escalation began at a dose of 240 mg/m2 evofosfamide and increased stepwise in a 3+3 design until reaching the MTD of 480 mg/m2. The recommended phase 2 dose (RP2D) was set at 340 mg/m2 and a dose expansion cohort of 15 treated patients were treated at the RP2D. Stage B dose escalation began at a dose of 240 mg/m2 and concluded at the 340 mg/m2 RP2D of stage A. There were no DLTs observed in this cohort. A total of 24 patients were treated at the RP2D. Results: Of the 31 patients treated on stage A, the median age was 65, with a range of 53-86. The median number of prior treatments was 6 (range: 2-13). Of the 28 patients treated on stage B, the median age was 62, with a range of 45-83. The median number of prior treatments was 8 (range: 3 - 16). All patients had prior bortezomib exposure with a median number of bortezomib containing regimens in stage B of 3 (range: 1-6). The most common stage A grade 3/4 events were anemia (36%), neutropenia (32%), thrombocytopenia (39%), leukopenia (23%), cellulitis (10%) and pneumonia (10%). Four pts (13%) discontinued due to an adverse event. The most common Arm B grade 3/4 events were thrombocytopenia (61%), neutropenia (32%), anemia (25%), leukopenia (18%) and pneumonia (14%). Two patients (7%) discontinued due to an adverse event. Of the 31 patients evaluable for response in stage A, 4 Partial Responses and 2 Minimal Responses were reported for a clinical benefit rate of 19%. Twenty patients (65%) in stage A had stable Disease. Of the 28 patients evaluable for response in stage B, 1 Complete Response, 2 Partial Responses and 2 Minimal Responses were reported for a clinical benefit rate of 18%. Eighteen patients (64%) in stage B had Stable Disease. Conclusion: A 340 mg/m2 twice a week dose of the hypoxia- activated agent evofosfamide was established as the recommended Phase 2 dose when combined with dexamethasone with or without bortezomib. Clinical activity was noted along with a majority of patients having stable disease or better even in this heavily pre-treated refractory population of MM. The use of hypoxia-activated agents holds promise as a novel therapeutic target in MM. Disclosures Raje: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Eli Lilly: Research Funding. Armand:Pfizer: Research Funding; Roche: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Infinity Pharmaceuticals: Consultancy; Sequenta Inc: Research Funding; Merck: Consultancy, Research Funding. Rosenblatt:BMS: Research Funding; Astex: Research Funding; DCPrime: Research Funding. Shain:Amgen/Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Takeda/Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Signal Genetics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Anderson:Oncopep: Other: Scientific Founder; Onyx: Membership on an entity's Board of Directors or advisory committees; Acetylon: Other: Scientific Founder; Sonofi Aventis: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Richardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ghobrial:Amgen: Honoraria; BMS: Honoraria, Research Funding; Novartis: Honoraria; Noxxon: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Research Funding.

Download Full-text