A Phase I Study of Ibrutinib and Lenalidomide in Patients with Relapsed and Refractory B-Cell Non-Hodgkin's Lymphoma

Abstract Introduction: Lenalidomide, an immunomodulatory agent, and ibrutinib, a selective and covalent inhibitor of Bruton’s tyrosine kinase, are orally bioavailable agents with promising single agent activity in relapsed/refractory B-cell NHL. We are conducting a phase I study of the combination of ibrutinib and lenalidomide to determine the maximum tolerated dose, dose limiting toxicities (DLT), and preliminary efficacy in patients with relapsed/refractory NHL. Methods: Patients with relapsed/refractory B-cell NHL including diffuse large B-cell (DLBCL), transformed, mantle cell, marginal zone, lymphoplasmacytic, and follicular lymphoma who have received at least one prior therapy were eligible. Prior autologous but not allogeneic stem cell transplant and prior lenalidomide were permitted. Prior ibrutinib, CNS involvement, and patients requiring anticoagulation were not permitted. ANC > 1000/mm3, platelets > 50,000/mm3, and creatinine < 2.0 mg/dL, ALT/AST ≤ 2.5 x ULN, bilirubin ≤ 1.5 x ULN, and ECOG PS 0-2 were required at study entry. Treatment consisted of escalating doses of lenalidomide days 1-21 and ibrutinib days 1-28 of a 28 day cycle. A standard 3+3 dose escalation schema was followed. DLTs were assessed during cycle 1 and included: treatment delays > 14 days for toxicity; grade 5 toxicity; tumor lysis syndrome requiring dialysis; tumor flare reaction nonresponsive to corticosteroids; ANC < 500 / mm3 or platelets <25, 000 / mm3 persisting > 7 days; grade 3 or 4 febrile neutropenia or infection; and any grade 3 or 4 non-hematologic toxicity with the exception of DVT, diarrhea, nausea, or vomiting amenable to medical therapy, correctable electrolyte abnormalities; grade 3 fatigue, or grade 3 maculopapular rash that resolved within 7 days. Patients without significant toxicity could continue treatment until disease progression. Response was assessed every 3 months for 12 months and then every 6 months until disease progression. Results: From September 2013 until July 2014, 13 patients have been treated. Median age is 68 years (range 45-85) with 9 males. Histologies include DLBCL (4), transformed (4), follicular (2), mantle cell (2), and lymphoplasmacyctic (1) lymphoma. Median number of prior therapies is 3 (range 2-9) with 4 patients having undergone prior autologous transplant. Four patients were treated at dose level (DL) 1 (lenalidomide 15 mg and ibrutinib 420 mg). One patient was replaced for rapid disease progression and 1 patient experienced DLT consisting of a grade 2 ischemic stroke while on aspirin with no history of cardiovascular disease that resulted in discontinuation of study therapy. As a result of this DLT, dose level 1 was expanded to 6 patients. A second DLT was observed, a grade 3 rash that resolved within 7 days with interruption of therapy but recurred with diffuse erythroderma within 4 hours of ibrutinib resumption on day 22 at 280 mg. A total of 6 patients were then treated at DL -1 (lenalidomide 10 mg and ibrutinib 280 mg), and no DLTs were encountered. Related grade 3-4 toxicities occurred in 4/13 patients (31%), including one patient with hypokalemia, neutropenia, thrombocytopenia, and pneumonia, two others with neutropenia and one with maculapapular rash. Patients have received a median of 3 cycles of therapy to date (range 1-5) and 5 remain on therapy. At DL 1, a patient with DLBCL achieved a complete response (CR) and patient with transformed follicular achieved a partial response (PR). At DL -1, a patient with DLBCL achieved a CR and a patient with mantle cell lymphoma achieved a PR. Four patients achieved stable disease. Reasons for study discontinuation include two patients with DLTs who were not evaluated for response, one patient with stable disease who went off study for alternative treatment, and five patients who have progressed. Conclusions: Combined therapy with lenalidomide and ibrutinib in patients with relapsed NHL has been well tolerated at doses of 10 mg and 280 mg respectively, although DLTs of recurrent rash and stroke were encountered with 15 mg lenalidomide and 420 mg ibrutinib. Dose escalation to an intermediate dose level with lenalidomide 10 mg and ibrutinib 420 mg is planned. If this dose level is deemed safe, intra-patient dose escalation of the lenalidomide from 10 mg in cycle 1 to 15 mg in cycle 2 with ibrutinib 420 mg continuously will be tested. Preliminary efficacy has been observed in patients with relapsed/refractory DLCL, MCL, and transformed NHL. Disclosures Christian: Janssen Research & Development, LLC: Research Funding; Celgene: Consultancy. Off Label Use: Use of lenalidomide and ibrutinib in B-cell non-Hodgkin's lymphoma. Smith:Celgene: Consultancy, Research Funding; Pharmacyclics/Janssen: Consultancy, Speakers Bureau. Porcu:Celgene: Honoraria. Byrd:Phamacyclics: Research Funding. Blum:Janssen, Pharmacyclics: Research Funding.

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Updated Results of a Phase I Study of Ibrutinib and Lenalidomide in Patients with Relapsed and Refractory B-Cell Non-Hodgkin's Lymphoma

Blood ◽

10.1182/blood.v126.23.3983.3983 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3983-3983 ◽

Cited By ~ 2

Author(s):

Beth A Christian ◽

John G. Kuruvilla ◽

Sonali M. Smith ◽

Pierluigi Porcu ◽

Kami J. Maddocks ◽

...

Keyword(s):

Phase I ◽

B Cell ◽

Disease Progression ◽

Dose Level ◽

Dose Escalation ◽

Research Funding ◽

Phase I Study ◽

Hematologic Toxicity ◽

Off Label ◽

Grade 3

Abstract Introduction: Lenalidomide, an immunomodulatory agent, and ibrutinib, a selective and covalent inhibitor of Bruton's tyrosine kinase, are orally bioavailable agents with single-agent activity in several histologic subtypes of relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). We are conducting a phase I study of the combination of ibrutinib and lenalidomide to determine the maximum tolerated dose, dose limiting toxicities (DLT), and preliminary efficacy in pts with relapsed/refractory NHL and updated results are presented. Methods: Patients (pts) with relapsed/refractory B-cell NHL including diffuse large B-cell (DLBCL), transformed, mantle cell (MCL), marginal zone (MZL), lymphoplasmacytic (LPL), and follicular (FL) lymphoma who have received at least one prior therapy were eligible. Prior autologous but not allogeneic stem cell transplant and prior lenalidomide were permitted. Prior ibrutinib, CNS involvement, and pts requiring anticoagulation were not permitted. ANC > 1000/mm3, platelets > 50,000/mm3, and creatinine < 2.0 mg/dL, ALT/AST ≤ 2.5 x ULN, bilirubin ≤ 1.5 x ULN, and ECOG PS 0-2 were required at study entry. Treatment consisted of escalating doses of lenalidomide days 1-21 and ibrutinib days 1-28 of a 28 day cycle. A standard 3+3 dose escalation schema was followed. DLTs included: treatment delays > 14 days for toxicity; grade 5 toxicity; tumor lysis syndrome requiring dialysis; tumor flare reaction nonresponsive to corticosteroids; ANC < 500/mm3 or platelets <25, 000/mm3 persisting > 7 days; grade 3 or 4 febrile neutropenia or infection; and any grade 3 or 4 non-hematologic toxicity with the following exceptions: DVT, diarrhea, nausea or vomiting amenable to medical therapy, correctable electrolyte abnormalities; grade 3 fatigue, or grade 3 maculopapular rash that resolved within 7 days. Pts without significant toxicity could continue treatment until disease progression. Response was assessed every 3 months for 12 months and then every 6 months until disease progression. Results: Twenty-five pts have been treated. Median age is 67 years (range 45-85) with 16 males. Histologies include DLBCL/transformed lymphoma (n=9), MCL (n=7), FL (n=4), MZL (n=2), and LPL (n=3). Four pts were treated at dose level (DL) 1 (lenalidomide 15 mg/ibrutinib 420 mg). One pt was replaced for rapid disease progression and 1 pt experienced DLT consisting of a grade 2 ischemic stroke. As a result of this DLT, DL 1 was expanded to 6 evaluable pts. A second DLT was observed, a grade 3 rash that resolved within 7 days but recurred on day 22. A total of 6 pts were then treated at DL-1 (lenalidomide 10 mg/ibrutinib 280 mg), and no DLTs were encountered. The protocol was amended to include additional dose levels. Pts enrolled on dose level -1A with lenalidomide 10 mg and ibrutinib 420 mg. One DLT occurred at this dose level, a grade 3 rash that failed to resolve within 7 days. The dose level was expanded to 6 pts without further DLT. DL-1B includes an intra-pt dose escalation of the lenalidomide from 10 mg in cycle 1 to 15 mg in cycle 2 with ibrutinib 420 mg. Six pts have been enrolled on this dose level. Three pts have been replaced including 2 with cytopenias not meeting DLT criteria but precluding dose escalation and one with progressive disease. Three pts at DL-1B remain on treatment. Related grade 3-4 toxicities occurred in 16/24 currently evaluated pts (67%), including primarily hematologic toxicity, rash, increased LFTs, pneumonia, hypokalemia, and syncope. Pts have received a median of 3 cycles of therapy to date (range 1-19) and 9 remain on therapy. At DL 1, a pt with DLBCL achieved a complete response (CR) and a pt with transformed follicular achieved a partial response (PR). At DL-1, a pt with DLBCL achieved a CR and 1 pt each with MCL and FL achieved PR. At DL -1A, 1 pt each with MCL and MZL achieved a PR. Overall response rate for 18 assessable pts is 39%. Five pts had best response of stable disease. Sixteen pts have discontinued the study including 3 pts with DLTs, 2 for alternative treatment, 2 for toxicity, and 9 pts with progression. Conclusions: Combined therapy with lenalidomide and ibrutinib in pts with relapsed NHL is well-tolerated, although DLTs of recurrent rash and stroke were encountered. Lenalidomide 10 mg and ibrutinib 420 mg was tolerated and pts are currently enrolling in an intra-pt dose escalation cohort. Preliminary efficacy has been observed in pts with relapsed/refractory DLBCL, MCL, FL, MZL, and transformed NHL. Disclosures Christian: Pharmacyclics: Research Funding; Acerta: Research Funding; Immunomedics: Research Funding; Celgene: Consultancy; Novartis: Other: IDSM; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding. Off Label Use: The use of ibrutnib and lenalidomide in combination in relapsed/refractory non-Hodgkin's lymphoma is off-label. Kuruvilla:Karyopharm: Honoraria, Research Funding; Roche Canada: Honoraria; Seattle Genetics: Honoraria, Research Funding. Smith:Celgene: Consultancy; Pharmacyclics: Consultancy. Porcu:Cell Medica: Research Funding; Infinity: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Shape: Research Funding. Maddocks:Acerta: Research Funding; Pharamcyclics: Research Funding; Novartis: Research Funding. Byrd:Pharmacyclics: Research Funding. Blum:Celgene: Research Funding; cephalon: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding.

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A Phase I Trial of the Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib (PCI-32765), in Combination with Rituximab (R) and Bendamustine in Patients with Relapsed/Refractory Non-Hodgkin's Lymphoma (NHL)

Blood ◽

10.1182/blood.v120.21.1643.1643 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1643-1643 ◽

Cited By ~ 7

Author(s):

Kristie A. Blum ◽

Beth Christian ◽

Joseph M. Flynn ◽

Samantha M. Jaglowski ◽

Jeffrey Alan Jones ◽

...

Keyword(s):

Phase I ◽

B Cell ◽

Dose Level ◽

Research Funding ◽

Phase I Study ◽

Single Agent ◽

Maximum Tolerated Dose ◽

Irreversible Inhibitor ◽

Grade 3 ◽

Dose Reductions

Abstract Abstract 1643 Introduction: Ibrutinib is an orally available, irreversible inhibitor of BTK, a downstream protein in the B-cell receptor signaling pathway critical for normal B-cell development. In a phase I study in patients with relapsed B-cell malignancies (Fowler ASH 2010), the overall response rate (ORR) was 43%, with responses observed in patients with relapsed mantle cell (MCL), diffuse large B-cell (DLBCL), follicular (FL), and marginal zone lymphoma (MZL). In a phase II single agent study in MCL (Wang ASH 2011), ORR was 67% with several responding patients remaining on ibrutinib over 1 year. Rituximab (R) and bendamustine is a highly active regimen with ORR ranging from 52–92% in patients with relapsed/refractory NHL. This phase I study was designed to determine the maximum tolerated dose, dose limiting toxicity (DLT), toxicities, and preliminary efficacy of R-bendamustine in combination with ibrutinib in patients with relapsed/refractory NHL. Methods: Eligibility included patients with relapsed/refractory FL, MZL, MCL, transformed NHL, and DLBCL, and patients with previously untreated MCL not candidates for autologous stem cell transplantation (ASCT). ANC ≥1000/mm3, platelets ≥50,000/mm3, and creatinine ≤ 2.0 mg/dL were required at study entry. Prior ASCT, rituximab, bendamustine, and ibrutinib were permitted. Treatment consisted of R 375 mg/m2 day 1, bendamustine 90 mg/m2days 1 and 2, and escalating doses of ibrutinib (280 mg or 560 mg) days 1–28 every 28 days for 6 cycles. Six patients were enrolled at each dose level. Responding patients could continue ibrutinib alone after cycle 6 until disease progression or unacceptable toxicity. Pegfilgrastim was permitted for patients with grade 4 neutropenia during cycles 1–6. Response was assessed after cycles 3 and 6 by International Harmonization Criteria (Cheson, JCO 2007). Results: Eleven patients (9 males) with a median age of 72 (range 45–84) previously treated with a median of 3 prior therapies (range 0–10) were enrolled. Six patients were refractory to their most recent therapy, 4 patients had prior ASCT, 2 patients had received prior bendamustine, and no patients had prior ibrutinib. Other characteristics included stage III-IV disease in 82%, extranodal involvement in 64%, elevated IPI ≥3 in 55%, bulky adenopathy ≥5 cm in 45%, B-symptoms in 45%, and elevated LDH in 36%. Histologies included MCL (n=3), DLBCL (n=3, all germinal center origin by Hans immunohistochemical criteria), transformed NHL (n=2), FL (n=2), MZL (n=1). Nine patients completed two or more cycles of therapy (median 3, range 1–6) with 280 mg of ibrutinib (n=6) and 560 mg of ibrutinib (n=3). Two patients who discontinued therapy prior to completing cycle 1 for progressive disease (PD) at 280 mg and 560 mg of ibrutinib, respectively, were replaced. Six patients continue to receive protocol treatment. The 5 patients off study included the 2 patients with DLBCL and transformed NHL who were replaced for PD prior to completing cycle 1, 2 patients with DLBCL and PD after cycles 3 and 4, and 1 patient with MCL receiving 280 mg ibrutinib with R-bendamustine who discontinued due to grade 3 neutropenia lasting > 14 days after cycle 4. No DLTs have been observed. Grade 3–4 events included lymphopenia (64%), neutropenia (27%), thrombocytopenia (18%), pancreatitis (9%), vomiting (9%), shingles (9%), and rash (9%). Dose reductions from 280 mg ibrutinib to 140 mg were required in 3 patients for grade 3 thrombocytopenia, pancreatitis, and rash. Bendamustine dose reductions to 60 mg/m2were required in 1 patient for grade 3 thrombocytopenia. ORR was 38% in 8 evaluable patients, with 3 patients currently receiving protocol treatment who have not yet undergone restaging scans. Responses included 2 complete responses and 1 partial response in the 3 patients with MCL. Conclusions: Combined ibrutinib with R-bendamustine appears well tolerated without unexpected toxicity and with preliminary activity in patients with previously untreated and relapsed MCL. Three additional patients will be accrued to the 560 mg dose level and expansion cohorts examining this combination specifically in patients with FL, DLBCL, and MCL are planned. Disclosures: Blum: Pharmacyclics: Research Funding. Off Label Use: Ibrutinib is not approved for the treatment of NHL. Jaglowski:Pharmacyclics: Research Funding. Maddocks:Pharmacyclics: Research Funding. Byrd:Pharmacyclics: Research Funding.

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A Phase I Study of IMGN529, an Antibody-Drug Conjugate (ADC) Targeting CD37, in Adult Patients with Relapsed or Refractory B-Cell Non-Hodgkin’s Lymphoma (NHL)

Blood ◽

10.1182/blood.v124.21.1760.1760 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1760-1760 ◽

Cited By ~ 13

Author(s):

Anastasios Stathis ◽

Arnold S. Freedman ◽

Ian W. Flinn ◽

Kami J. Maddocks ◽

Steven Weitman ◽

...

Keyword(s):

B Cells ◽

Phase I ◽

B Cell ◽

Dose Escalation ◽

Early Onset ◽

Research Funding ◽

Phase I Study ◽

Maximum Tolerated Dose ◽

Autologous Transplant ◽

Grade 3

Abstract Background: While CD37 is widely expressed on malignant B cells in NHL and chronic lymphocytic leukemia (CLL), few therapies are in development exploiting this target. In normal tissues, high CD37 expression is restricted to blood cells and lymphoid tissues, making CD37 well suited to an ADC approach. IMGN529 is a CD37-targeting ADC consisting of a CD37-binding antibody with intrinsic pro-apoptotic and immune effector activities conjugated to the maytansinoid anti-mitotic, DM1. Its unique profile enables IMGN529 to potentially kill CD37-positive B cells via multiple mechanisms of action. In preclinical studies, IMGN529 exhibits targeted, potent activity against NHL cells via direct inhibition of cell survival and effector function by its antibody and tubulin-disruption by DM1. Methods: A Phase I study is being conducted to evaluate safety, pharmacokinetics, pharmacodynamics, exploratory biomarkers and preliminary evidence of activity of IMGN529 and to determine the maximum tolerated dose/recommended phase 2 dose of IMGN529 in adult patients (pts) with relapsed or refractory NHL. IMGN529 is given intravenously on Day (d) 1 of each 21d cycle (C). Efficacy is evaluated based on Cheson response criteria. CD37 is being evaluated by IHC in available tumor samples to assess expression of CD37 among different NHL subtypes. Results: To date, 31 pts have been enrolled (66% male), median age of 65 years: Diffuse large B-cell (DLBCL, n = 14), Follicular lymphoma (FL, n = 10), MCL (n = 5), MZL (n = 2). Dose escalation began at 0.1 mg/kg. Early onset, transient grade 3-4 neutropenia was reported in 6 patients receiving doses at or below 0.8 mg/kg, potentially attributed to cytokine release. Peri-infusional steroid administration was added to the study protocol, and the incidence and severity of this neutropenia was significantly reduced. Additional patients have been enrolled and increasingly higher dose levels evaluated. To date the highest dose evaluated is 1.0 mg/kg. Cytokine levels are currently being evaluated in trial patients to gain a better understanding of the mechanisms underlying the early onset neutropenia. At the 1.0 mg/kg dose cohort grade 3-4 neutropenia was reported (1 DLT of febrile neutropenia among 6 patients) around d10 of the cycle and granulocyte colony stimulating factor (G-CSF) was added as primary prophylaxis. The most common treatment-emergent adverse events (AEs) occurring in ≥ 20% of the 31 pts enrolled were neutropenia (30%), fever (27%), asthenia (20%) and fatigue (20%). A reduction in lymphocyte count seen early after dosing (d2) in the majority of pts suggests a CD37-mediated reduction in lymphocytes, consistent with the mechanism of action of a CD37-targeted therapy. Four objective responses have been reported in patients who had received multiple lines of prior therapy. At the 1.0 mg/kg dose level, two patients with DLBCL who were heavily pretreated and who relapsed following autologous transplant have achieved an objective response that is ongoing. One pt has achieved a PR and one patient has achieved a CR. As previously reported, at doses of 0.2 mg/kg and 0.4 mg/kg one pt with transformed FL, who progressed following an autologous transplant, and one pt with DLBCL achieved a PR. The maximum tolerated dose has not yet been achieved and dose escalation is ongoing with additional data expected. Conclusions: IMGN529, a CD37-targeting ADC, demonstrates clinical activity in patients with NHL and has the potential to be a novel therapeutic for B-cell lymphoproliferative malignancies. Disclosures Stathis: ImmunoGen, Inc: Travel assistance Other; Pfizer: Research Funding; Oncoethix SA: Research Funding. Flinn:ImmunoGen, Inc: Research Funding. Maddocks:Pharmacyclics, Seattle Genetics, MorphoSys: Advisory Board Other, Research Funding. Zucca:Roche, Mundipharma, Novartis, Jannsen, Celgene: Consultancy, Honoraria, Research Funding, travel assistance Other. Romanelli:ImmunoGen, Inc.: Employment, Equity Ownership; sanofi: Employment. Zildjian:ImmunoGen, Inc: Employment. Ruiz-Soto:ImmunoGen, Inc: Employment; Sanofi: Past employment within 1 year, Past employment within 1 year Other.

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Phase I Study of ATR Inhibitor M6620 in Combination With Topotecan in Patients With Advanced Solid Tumors

Journal of Clinical Oncology ◽

10.1200/jco.2017.76.6915 ◽

2018 ◽

Vol 36 (16) ◽

pp. 1594-1602 ◽

Cited By ~ 38

Author(s):

Anish Thomas ◽

Christophe E. Redon ◽

Linda Sciuto ◽

Emerson Padiernos ◽

Jiuping Ji ◽

...

Keyword(s):

Lung Cancer ◽

Phase I ◽

Small Cell Lung Cancer ◽

Dose Level ◽

Dose Escalation ◽

Stable Disease ◽

Phase I Study ◽

Small Cell ◽

Small Cell Lung ◽

Platinum Refractory

Purpose Our preclinical work identified depletion of ATR as a top candidate for topoisomerase 1 (TOP1) inhibitor synthetic lethality and showed that ATR inhibition sensitizes tumors to TOP1 inhibitors. We hypothesized that a combination of selective ATR inhibitor M6620 (previously VX-970) and topotecan, a selective TOP1 inhibitor, would be tolerable and active, particularly in tumors with high replicative stress. Patients and Methods This phase I study tested the combination of M6620 and topotecan in 3-week cycles using 3 + 3 dose escalation. The primary end point was the identification of the maximum tolerated dose of the combination. Efficacy and pharmacodynamics were secondary end points. Results Between September 2016 and February 2017, 21 patients enrolled. The combination was well tolerated, which allowed for dose escalation to the highest planned dose level (topotecan 1.25 mg/m2, days 1 to 5; M6620 210 mg/m2, days 2 and 5). One of six patients at this dose level experienced grade 4 thrombocytopenia that required transfusion, a dose-limiting toxicity. Most common treatment-related grade 3 or 4 toxicities were anemia, leukopenia, and neutropenia (19% each); lymphopenia (14%); and thrombocytopenia (10%). Two partial responses (≥ 18 months, ≥ 7 months) and seven stable disease responses ≥ 3 months (median, 9 months; range, 3 to 12 months) were seen. Three of five patients with small-cell lung cancer, all of whom had platinum-refractory disease, had a partial response or prolonged stable disease (10, ≥ 6, and ≥ 7 months). Pharmacodynamic studies showed preliminary evidence of ATR inhibition and enhanced DNA double-stranded breaks in response to the combination. Conclusion To our knowledge, this report is the first of an ATR inhibitor-chemotherapy combination. The maximum dose of topotecan plus M6620 is tolerable. The combination seems particularly active in platinum-refractory small-cell lung cancer, which tends not to respond to topotecan alone. Phase II studies with biomarker evaluation are ongoing.

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Combined Autophagy and Proteasome Inhibition for Multiple Myeloma: Final Results of a Phase 1 Trial of Hydroxychloroquine and Standard Dose Bortezomib for Patients with Relapsed or Refractory Myeloma

Blood ◽

10.1182/blood.v118.21.1869.1869 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1869-1869 ◽

Cited By ~ 1

Author(s):

Dan T. Vogl ◽

Edward A. Stadtmauer ◽

James Bradner ◽

Lisa Davis ◽

Thomas M. Paul ◽

...

Keyword(s):

Bone Marrow ◽

Disease Progression ◽

Dose Level ◽

Stable Disease ◽

Peripheral Blood ◽

Research Funding ◽

Plasma Cells ◽

Proteasome Inhibition ◽

Bone Marrow Plasma ◽

Grade 3

Abstract Abstract 1869 BACKGROUND: The aggresome/autophagy pathway is the primary mechanism for disposal of ubiquitinated proteins for cells exposed to proteasome inhibition. Preclinical evidence shows that combining inhibition of the proteasome with bortezomib (Bz) and inhibition of autophagy with the anti-malarial drug hydroxychloroquine (HCQ) leads to enhanced cytotoxicity in myeloma cells. METHODS: Patients with relapsed or refractory myeloma enrolled on a standard 3+3 dose escalation design. Patients received 2-weeks of single-agent oral HCQ, followed by the addition of Bz on days 1, 4, 8, and 11 of 21-day cycles. HCQ and Bz doses were determined by dose level: (1) 200 mg qod / 1.0 mg/m2, (2) 200 qod / 1.3, (3) 200 qd / 1.3, (4) 200 bid / 1.3, (5) 400 bid / 1.3, (6) 600 bid / 1.3. Dose-limiting toxicity (DLT) was defined as grade ≥3 toxicity probably related to study therapy and occurring during the first 5 weeks, with the exception of any anemia or lymphopenia, neutropenia responsive to growth factor, platelets >10,000/mm3 not associated with bleeding, or gastrointestinal complaints relieved by symptomatic therapy. We used electron microscopy to characterize changes in autophagic vesicles in serial samples of peripheral blood mononuclear cells and CD138-selected bone marrow plasma cells. RESULTS: We enrolled 25 patients between 1/2008 and 2/2011, of which 21 patients completed at least 1 cycle of combined therapy and were evaluable for toxicity. The median duration of study participation was 14 weeks (range 1–77). Reasons for study discontinuation were side effects of therapy (6), lack of response (7), disease progression (11), and non-compliance (1). No protocol-defined dose limiting toxicities occurred, and the maximum tolerated dose was determined to be the top dose level of Bz 1.3 mg/m2 and HCQ 600 mg twice daily. Hematologic abnormalities were generally more attributable to disease progression than to treatment toxicity, but at the top dose level one patient had grade 3 thrombocytopenia and neutropenia after starting with a normal platelet count and ANC, without evidence of progression through therapy. At the top dose level, gastrointestinal toxicities predominated, including 5 out of 6 evaluable patients with some form of grade 3 GI toxicity. Treatment emergent neuropathy occurred in 7 patients but was restricted to grade 1 or 2 and was easily managed with dose reduction of the Velcade. Three patients came off study before receiving the combined regimen and were not evaluable for response. The best responses for the remaining 22 patients included 3 near complete responses (nCR), 3 minor responses (MR), 9 stable disease (SD), and 7 progression (PD). The 3 nCRs occurred in Bz-naïve patients receiving HCQ at 400 mg/d (1 pt) and 1200 mg/d (2 pts). Two patients who had previously progressed while receiving weekly maintenance Bz had MRs on study, including one who maintained a MR for over 7 months. Three additional Bz-refractory patients initially achieved stable disease during study treatment, with on study TTP of 8 weeks (at HCQ 1200 mg/d), 15 weeks (100 mg/d), and 17 weeks (200 mg/d). Preliminary analyses of vesicle counts at HCQ doses up to 800 mg/d identify individual patients with increases in autophagic vesicles in either peripheral blood or bone marrow plasma cells, but these are not consistent, nor is there any evident correlation with response. CONCLUSION: Combined Bz and HCQ is tolerable, with a phase 2 dose of Bz 1.3 mg/m2 and HCQ 1200 mg/d and likely hematologic and gastrointestinal DLTs. There is a suggestion of improved efficacy over Bz alone, with minor responses and long periods of stable disease in Bz-refractory patients. Final analysis of autophagy inhibition in correlative specimens, including the top dose cohort, will be available for the meeting. Disclosures: Vogl: Millennium Pharmaceuticals: Honoraria, Research Funding. Off Label Use: Hydroxychloroquine is FDA approved for treatment of malaria and rheumatoid arthritis. This paper discusses its use in treatment of myeloma. Carroll:Agios Pharmaceuticals: Research Funding; TetraLogic Pharmaceuticals: Research Funding; Sanofi Aventis Corporation: Research Funding; Glaxo Smith Kline, Inc.: Research Funding. Amaravadi:Millennium Pharmaceuticals: Honoraria, Research Funding.

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Preliminary Results of a Phase I Study of Obinutuzumab, Venetoclax, and Lenalidomide in Relapsed and Refractory B-Cell Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood-2018-99-117172 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4185-4185 ◽

Cited By ~ 1

Author(s):

Kami J. Maddocks ◽

Farrukh T. Awan ◽

Ying Huang ◽

Sabarish Ayyappan ◽

Robert A Baiocchi ◽

...

Keyword(s):

Phase I ◽

B Cell ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Phase I Study ◽

Hematologic Toxicity ◽

Tumor Lysis ◽

Genetics Research ◽

Non Hodgkin Lymphoma ◽

Grade 3

Abstract Introduction: Combined obinutuzumab (O) and lenalidomide (L) has demonstrated safety and preliminary efficacy in follicular lymphoma1. Venetoclax (V), a BCL2 inhibitor, as a single agent2 and in combination with rituximab3 is under development in several subtypes of B-cell non-Hodgkin lymphoma (NHL). We are conducting a phase I study of the combination of O, V, and L to determine the maximum tolerated dose, dose-limiting toxicities (DLT), and preliminary efficacy. Methods: Pts with relapsed/refractory diffuse large B-cell (DLBCL), transformed, high grade B-cell, Burkitt, marginal zone, and follicular (FL) lymphoma who have received ≥ 1 prior therapy were eligible. Prior autologous but not allogeneic stem cell transplant were permitted. Prior L or BCL2 family inhibitors, CNS involvement, and active hepatitis or HIV infection were not permitted. ANC > 1000/mm3, platelets > 75,000/mm3, creatinine clearance ≥50 ml/min, ALT/AST ≤ 3 x ULN, bilirubin ≤ 1.5 x ULN, and ECOG PS 0-2 were required at study entry. Treatment consisted of escalating doses of L days 1-21 and V days 1-28 of a 28 day cycle (Table 1). O 1000 mg was administered on days 1, 8 and 15 of cycle 1 and then on day 1 of cycles 2-6. A 3+3 dose escalation schema was followed. DLTs included: treatment delays > 28 days; ANC < 500 / mm3 or platelets <25, 000 / mm3 persisting > 28 days; grade 4 febrile neutropenia or infection or grade 3 that fails to resolve within 7 days; and any grade 3 or 4 non-hematologic toxicity with the following exceptions: DVT, tumor flare reaction controllable with steroids, tumor lysis syndrome that does not require dialysis, diarrhea, nausea, or vomiting responsive to medical treatment, transient electrolyte abnormalities or elevations of ALT / AST that resolve ≤ grade 1 within 48 hours, grade 3 infusion reactions responsive to medical therapy. Pts without significant toxicity or progression could continue treatment up to 12 cycles. Response was assessed every 3 months for 12 months and then every 6 months until disease progression. Results: 14 pts have been treated. Median age is 61 years (range 35-78 years) with 10 males. Median prior therapies is 2 (range 1-10). 5 pts had bulky disease (≥ 7.5 cm) and median baseline lactate dehydrogenase was 274 U/L (range 151-894, 12/14 above ULN 190 U/L). 10 pts were refractory to their last therapy. Histologies include DLBCL/transformed lymphoma (n=11) and FL (n=3). 3 pts were treated at dose level (DL) 1 (V 400 mg / L 15 mg). One pt experienced DLT, grade 3 neutropenic fever lasting > 7 days. DL 1 was expanded and no additional DLTs occurred. One pt with DLBCL was replaced for disease progression. 4 pts were then treated at DL 2 (V 600 mg / L 15 mg), and no DLTs were encountered. One pt was replaced due to missed doses of the oral agents. A total of 3 pts have been treated at DL 3 (V 800 mg / L 15 mg) and no DLTs have occurred at the time of data cutoff. Related grade 3-4 toxicities were primarily hematologic including neutropenia (n= 11, 78.6%), anemia (n=1, 7%), and thrombocytopenia (n=2, 14.3%). Grade 3-4 infections included sepsis, febrile neutropenia, pneumonia and a urinary tract infection. No clinically significant tumor lysis has occurred. Pts have received a median of 3 cycles (range 1-12) and 4 remain on therapy. Five pts have achieved a response. At DL 1, a pt with DLBCL, GC type, achieved a complete response (CR) and 2 pts with transformed FL achieved a partial response (PR). At DL 2, 1 pt with FL achieved a CR. At DL 3, 1 pt with transformed FL/double hit achieved a PR. Ten pts have discontinued, 6 with progression and 1 for DLT, alternative treatment, physician preference, and diagnosis of MDS in a patient with 3 prior lines of chemotherapy, respectively. Conclusions: Combined treatment with O, V, and L administered up to 12 cycles has been feasible with hematologic toxicity being the most common adverse event. Enrollment is ongoing and will include expansion cohorts in FL and DLBCL.Fowler et al. Activity of the immunologic doublet of lenalidomide plus obinutuzumab in relapsed follicular lymphoma: Results of a phase I/II study. JCO 2015; 35: 7531.Gerecitano et al. A Phase 1 Study of Venetoclax (ABT-199 / GDC-0199) Monotherapy in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma. Blood 2015; 126: 254.Zinzani et al. Phase 2 Study of Venetoclax Plus Rituximab or Randomized Ven Plus Bendamustine+Rituximab (BR) Versus BR in Patients with Relapsed/Refractory Follicular Lymphoma: Interim Data. Blood 2016; 128:617. Disclosures Maddocks: Merck: Research Funding; Pharmacyclics/Janssen: Honoraria; BMS: Research Funding; Pharmacyclics: Research Funding; Teva: Honoraria; Novartis: Research Funding; AstraZeneca: Honoraria. Jaglowski:Juno: Consultancy; Kite Pharma: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Blum:Celgene: Research Funding; Novartis: Research Funding; Morphosys: Research Funding; Seattle Genetics: Research Funding. Christian:Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Acerta: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Immunomedics: Research Funding.

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A Phase I/II Trial of Combination Gemcitabine and Bortezomib (VELCADE®) for Relapsed/Refractory T-Cell Non-Hodgkin Lymphoma (NHL) and Aggressive B-Cell NHL

Blood ◽

10.1182/blood.v118.21.1646.1646 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1646-1646

Author(s):

Andrew M. Evens ◽

Steven T. Rosen ◽

Leo I. Gordon ◽

Irene Helenowski ◽

Justin Kline ◽

...

Keyword(s):

Clinical Trial ◽

T Cell ◽

Phase I ◽

B Cell ◽

Dose Escalation ◽

Research Funding ◽

Treatment Cycle ◽

Treatment Schedule ◽

Dosing Schedule ◽

Grade 3

Abstract Abstract 1646 Background: NF-κB has been shown to be deregulated in B-NHL and T-NHL subtypes. The proteasome inhibitor, bortezomib, has the capacity to reverse the downstream consequences of NF-κB, while gemcitabine has documented single-agent activity in relapsed/refractory NHL. Further, in vitro and murine xenograft tumor models have demonstrated synergy between these two agents. Based on these data, and the continued unmet clinical need for patients with relapsed/refractory aggressive NHL either ineligible for or relapsed after stem cell transplant (SCT), we conducted a phase I/II trial utilizing this novel combination. Methods: This was a phase I/II investigator-initiated clinical trial conducted through two centers. The phase I design was a classic 3+3 with dose escalation of bortezomib (1.3 mg/m2 to 1.6 mg/m2 given day (D) 1 and D8) with static gemcitabine dosing (800 mg/m2 D1 and D8) given on q 21 day cycles. The definition of dose limiting toxicity (DLT) was: a) grade 3 or 4 non-hematologic toxicity (other than grade 3 nausea or vomiting); b) grade 4 vomiting despite maximal anti-emetic support; c) grade 4 neutropenia on D1 of a treatment cycle (despite growth factor support); and d) grade 4 thrombocytopenia on D1 of a treatment cycle. Following completion of bortezomib escalation, a planned phase II expansion of the study was planned. The null hypothesis was that the true success was less than or equal to 15% and the alternate hypothesis was that the true success was 40% or higher; type I error of 5% and a power of 80% was assumed. Results: From April 2006 to December 2010, we enrolled 32 relapsed/refractory NHL pts onto this phase I/II clinical trial. Sixteen pts had T-NHL (n=12 peripheral T-NHL NOS and n=1 each with angioimmunoblastic T-NHL, NK-/T-NHL, transformed large cell [from pre-existing cutaneous T-cell], and hepatosplenic) and 16 had B-NHL (all relapsed/refractory DLBCL). There were 16 women and 16 men with a median age of 61 years (range, 37–85 years). The median ECOG performance status was 1 (range, 0–2), median prior therapies were 2.5 (range, 1–5), while 35% had failed prior autologous SCT. During the initial phase I dose escalation, 2 DLTs were noted (grade 3 hypertension and grade 3 elevation of liver function tests), while a maximally tolerated dose was not identified. However, among the first 18 pts treated on the D1+D8 (q21 day) dosing schedule, 67% experienced grade 3/4 neutropenia and/or grade 3/4 thrombocytopenia, primarily on D8 of treatment cycles. These recurrent D8 cytopenias resulted in repeated treatment delay(s). The median number of cycles delivered for these 18 pts were 1.0 (due to hematotoxicity), which was associated with a low (59%) median normalized dose-intensity. Thus, in early 2009, the clinical trial was amended instituting a modified treatment schedule of gemcitabine 800 mg/m2 and bortezomib 1.6 mg/m2 to both be administered on D1 and D15 of a 28-day schedule for an additional 22 patients. Treatment-related toxicity was markedly reduced using this modified treatment schedule; only one grade 3 event each of anemia and thrombocytopenia were recorded. However, after 14 pts had accrued to the modified treatment schedule, efficacy data were analyzed by the Northwestern University Data Monitoring Committee (DMC). Among all 32 patients, the ORR was 16% (complete remission (CR) 13%). Further, the ORR for all B-NHL pts was 6% (no CR) and 25% for T-NHL (19% CR). On the modified D1+D15 treatment schedule, the ORR for B-NHL was 0% (0/8); while among T-NHL, the ORR was 50% (3/6) with each of these latter pts remaining in continued remission at 29+, 26+, and 19+ months. Nevertheless, an analysis performed by the DMC for the overall study conduct recommended premature study closure; thus the final planned 8 pts did not enroll. Conclusions: We determined in this phase I/II study for pts with relapsed/refractory, aggressive T-NHL and B-NHL that combined bortezomib/gemcitabine using a dosing schedule of D1+8 q21 days was not tolerated and is not recommended for further study. Modification of bortezomib/gemcitabine dosing to D1+15 q28 days was tolerated markedly better, allowing consistent treatment delivery. Altogether, clinical efficacy of gemcitabine plus bortezomib in aggressive B-NHL was low (with either schedule), while there was a potential signal of activity with durable responses in a small number of pts in the T-NHL population utilizing the modified treatment schedule. Disclosures: Evens: Millennium: Research Funding, advisory board. Off Label Use: Velcade in T-cell and aggressive (non-MCL) B-cell NHL. Winter:Millennium: Research Funding. Smith:Millennium: Research Funding.

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Oral Formulation of Rigosertib (ON 01910.Na) in Patients with Myelodysplastic Syndrome (MDS) – Phase I Study Results,

Blood ◽

10.1182/blood.v118.21.3797.3797 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3797-3797

Author(s):

Rami S. Komrokji ◽

Alan F. List ◽

Francois Wilhelm ◽

Jeffrey E. Lancet ◽

Azra Raza

Keyword(s):

Phase I ◽

Dose Level ◽

Dose Escalation ◽

Research Funding ◽

Oral Formulation ◽

Refractory Anemia ◽

Absolute Bioavailability ◽

History Of ◽

Grade 3 ◽

Dose Levels

Abstract Abstract 3797 Background: Rigosertib (ON 01910.Na) is a multi-kinase inhibitor that selectively induces mitotic arrest leading to apoptosis in cancer cells and myeloblasts, while non-toxic to normal cells. Biological activity of the intravenous formulation has been demonstrated in myelodysplastic syndromes (MDS), including an ongoing randomized clinical trial in patients with refractory anemia and excess blasts failing azanucleosides. We report the preliminary results of a safety and efficacy study of a novel oral formulation of rigosertib. Methods: The trial is a 3 part phase I dose escalation study. The first part addressed bioavailability and tolerability of single oral dosing administered on a weekly basis for 5 weeks, the second included dose escalation, the third represented a dose expansion of the recommended phase 2 dose (RP2D) with absolute biavailability and food/fasting bioavailability studies. Eligibility included any International prognostic Scoring System (IPSS) MDS risk group with at least one cytopenia, failure to respond to at least one prior standard treatment, good performance status (ECOG≤ 2), adequate kidney and liver functions. Key exclusions included hypoplastic MDS (< 10% cellularity), ascites, history of seizures, uncontrolled hypertension, and history of HIV. Dose limiting toxicity (DLT) was defined as grade 3 or greater non-hematological drug related toxicity or delay in blood count recovery for more than 30 days in the absence of response. Rigosertib dose was escalated based on a defined escalation dose schema (70, 140, 280, 560, and 700 mg). The drug was administered orally twice a day for 14 days of a 21 day cycle. Results: Between January 2010 and July 2011, 33 MDS patients were enrolled in an ongoing phase I dose escalating study. Pharmacokinetic dose proportionality was established in the 70–700 mg single dose range in the first 3 patients, and pharmacodynamically active concentrations were reached. A subsequent escalation phase enrolled 15 patients who were treated with 70 to 700 mg doses of rigosertib capsules bid for 2 weeks of a 3 week cycle (70mg: N=3; 140 mg: N=2; 280mg: N=2; 560: N=2; 700mg: N=6). The formulation was well tolerated. One patient experienced DLT at the 700mg dose level during the first 3-week cycle (dysuria and shortness of breath). Another patient at this dose level had grade 3 dysuria during cycle 2. The RP2D was identified as 560 mg bid and 18 patients were enrolled in the expansion cohort (part 3). Up to 12 patients in this cohort are undergoing full pharmacokinetic evaluation (absolute bioavailability vs. the IV formulation and food effect). Encouraging signs of activity have been observed, including two marrow CR responses at the 140 and 560 mg dose levels; erythroid response (reduction of at least 4 units of RBC transfusions over 56 days) in four Low/Int-1 risk transfusion dependent MDS patients (3 at 560mg and 1 at 700 mg dose levels). Full PK results as well as clinical activity and tolerability at the RP2D dose level will be presented. Conclusion: Oral rigosertib is bioavailable and well tolerated. The RP2D was 560 mg bid for 2 weeks of a 3 week with a DLT of dysuria. Early encouraging responses are being confirmed in the expansion phase of the study. Disclosures: Komrokji: Onconova Therapeutics: Research Funding. List:Onconova Therapeutics: Research Funding. Wilhelm:Onconova Therapeutics: Employment, Equity Ownership. Lancet:Onconova Therapeutics: Research Funding. Raza:Onconova Therapeutics: Research Funding.

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Phase I Trial of Ibrutinib, Lenalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM)

Blood ◽

10.1182/blood-2019-128233 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1912-1912

Author(s):

Sikander Ailawadhi ◽

Aneel Paulus ◽

Victoria R. Alegria ◽

Betsy Laplant ◽

Muhamad Alhaj Moustafa ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Phase I ◽

B Cell ◽

Dose Escalation ◽

Research Funding ◽

Cell Transplant ◽

B Cell Malignancies ◽

Minor Response ◽

Grade 3

Background: Ibrutinib (ibr) is a small-molecular inhibitor of Bruton's Tyrosine Kinase (BTK), active in the treatment of various B-cell malignancies. B-cell receptor signaling blockade by BTK inhibition using ibr down regulates IRF4 (survival transcription factor) which is down regulated by lenalidomide (R) as well, suggesting possible synergistic effect on cell death. Higher doses of ibr (560-840 mg daily) have been used in combination regimens for MM with no significant dose-limiting toxicities (DLTs) but the combination of ibr and len has not been previously tested. We present safety and preliminary efficacy of the combination ibr, R, and dexamethasone (d) in RRMM patients. Methods: This is a phase I dose escalation study (NCT03015792) of 28-day cycles of ibr (420 mg daily, 560 mg daily, 700 mg daily or 840 mg daily) days 1-28 in combination with R 25 mg PO days 1-21, and d 40 mg PO weekly utilizing a 3+3 dose-escalation design. Eligible RRMM patients had progression after ≥2 prior lines of treatment, measurable disease as per International Myeloma Working Group criteria, ECOG performance status ≤2, adequate bone marrow (BM) (absolute neutrophil count ≥1.0 x 109, platelets ≥50,000 cells/mm3 for patients with BM plasmacytosis <50% or ≥30,000 cells/mm3 for patients with BM plasmacytosis ≥50%), kidney (creatinine clearance ≥30 mL/min), and liver function [total bilirubin ≤1.5 x upper limit of normal (ULN), aspartate aminotransferase and alanine aminotransferase ≤3 x ULN], and PT/INR ≤1.5 X ULN. Treatment was to be continued till progressive disease (PD) or any unacceptable toxicity. The primary objective was to determine the maximum tolerated dose (MTD) of ibr+Rd in RRMM and secondary objective was to evaluate safety profile of this regimen. Results: As of July 26 2019, 18 patients had been enrolled in the trial. Three patients had to be replaced (2 at 700 mg cohort, 1 each due to withdrawal and ineligibility, and 1 at 840 mg due to withdrawal). Median age of all patients was 67 years (range 49-79) with 9 of the 15 evaluable patients being females. Evaluable patients as per ibr dose level included 3 at 420 mg, 3 at 560 mg, 3 at 700 mg, and 6 at 840 mg. Four out of 15 patients had high-risk cytogenetics. Median prior lines of treatment were 4 (range 2-13) and prior treatments included bortezomib in 87% (n=13), carfilzomib in 47% (n=7), ixazomib in 47% (n=7), lenalidomide in 87% (n=13), pomalidomide in 40% (n=6), thalidomide in 40% (n=6), daratumumab in 60% (n=9), and stem cell transplant in 53% (n=8). High risk cytogenetics [del 17p, t(4;14), t(14;16), t(14;20)] were noted in 4 of the 15 evaluable patients (27%). Median follow up for alive patients was 8.6 months (range 1.1-25.1 months) and the median number of treatment cycles was 2 (range 1-5). Most common reason for treatment discontinuation was PD (40%) followed by adverse events (AEs) (26.7%). Only 1 DLT possibly related to ibr was a grade 3 rash at the 840 mg dose. Grade 3/4 AEs at least possibly related to study treatment included anemia (n=3), thrombocytopenia (n=3), neutropenia (n=3), leucopenia (n=3), lymphopenia (n=2), febrile neutropenia (n=1), and rash (n=2). Overall, the most common all grade AEs included anemia (n=12), thrombocytopenia (n=10), fatigue (n=10), neutropenia (n=8), leucopenia (n=5), and diarrhea (n=5). (Figure 1) No treatment-related deaths were noted. Overall response rate (ORR) was 7% with partial response (PR) noted in 1 patient. Additionally, 1 patient achieved a minor response (MR) and 10 patients had stable disease (SD) for a clinical benefit rate (CBR) of 80%. (Figure 2) PD was noted in 1 patient and 2 patients did not get response assessment. Ibr 840 mg (daily) with R 25 mg (days 1-21) and d 40 mg weekly was considered the MTD of this regimen. The median progression-free survival (PFS) for the 15 evaluable patients was 4.5 months (95% CI: 1.8-not reached). Conclusions: We report the first phase 1 trial of combining a BTK inhibitor with Rd in RRMM patients. MTD of ibr was determined as 840 mg (daily) in combination with R 25 mg (days 1-21) and d 40 mg weekly. This dose of ibr is consistent with some other trials showing the benefit of a higher dose of ibr in various regimens for treatment of B-cell malignancies. We noted this regimen to be well-tolerated without much high-grade AEs. Disease stabilization was noted in majority of patients. These data lay the basis for a larger trial in a more uniform cohort of patients to better define the efficacy of this regimen. Disclosures Ailawadhi: Celgene: Consultancy; Amgen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy. Chanan-Khan:AbbVie: Research Funding; Xencor: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Jansen: Research Funding; Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding. OffLabel Disclosure: Ibrutinib is not FDA-approved for the treatment of multiple myeloma. The regimen of ibrutinib with lenalidomide and dexamethasone is not FDA-approved for the treatment of multiple myeloma.

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Weekly Carfilzomib, Cyclophosphamide and Dexamethasone (wCCd) in Newly Diagnosed Multiple Myeloma Patients: A Phase I- II Study

Blood ◽

10.1182/blood.v124.21.175.175 ◽

2014 ◽

Vol 124 (21) ◽

pp. 175-175 ◽

Cited By ~ 4

Author(s):

Antonio Palumbo ◽

Davide Rossi ◽

Sara Bringhen ◽

Alessandra Larocca ◽

Fabiana Gentilini ◽

...

Keyword(s):

Partial Response ◽

Phase I ◽

Board Of Directors ◽

Dose Level ◽

Dose Escalation ◽

Research Funding ◽

Maximum Tolerated Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

Grade 3

Abstract Background Carfilzomib is a novel second generation proteasome-inhibitor with significant anti MM activity and favorable toxicity profile, including very limited neurotoxicity and neutropenia. This Phase I/II study was designed to determine the maximum tolerated dose (MTD) of once weekly carfilzomib combined with cyclophosphamide-dexamethasone (wCCd) and to assess safety and efficacy of this combination in elderly patients with newly diagnosed MM. Here we report the first findings from the Phase I dose-escalation and expansion portions. Enrolment in the phase II portion is ongoing. Methods In the Phase I, the standard 3+3 dose-escalation scheme was adopted, with Carfilzomib as the only escalating agent starting at 45 mg/m2 (level 0), maximal planned dose 70 mg/m2 (level 2), and 36 mg/m2, if needed (level -1), given IV on days 1, 8, 15 in 28-day cycles. Oral cyclophosphamide was administered at 300 mg/m2 on days 1, 8, 15 and oral dexamethasone at 40 mg on days 1, 8, 15, 22 for all dose levels. Dose escalation of Carfilzomib was based on dose-limiting toxicities (DLTs) occurring in cycle 1. After completion of 9 cycles, patients receive 28-day maintenance cycles with Carfilzomib (days 1, 8, 15) at the maximum tolerated dose (MTD) defined by the Phase I study until disease progression or intolerance. The objectives were to determine the MTD and assess activity and safety. Results As of June 15, 2014, 28 newly diagnosed MM patients were enrolled. Median age was 74 years, 29% of patients were older than 75 years, 36% had ISS stage III, 24% had unfavorable FISH profile [t(4;14) or t (14;16) or del17p]. Twelve patients were enrolled in the Phase I portion of the study. At dose level 0 (Carfilzomib 45 mg/m2) no DLT was reported; at dose level 1 (Carfilzomib 56 mg/m2), 1 of 6 patients experienced DLT, consisting of grade 3 creatinine increase; at dose level 2 (Carfilzomib 70 mg/m2) no DLT occurred. The MTD of weekly Carfilzomib was thus established as 70 mg/m2. Toxicity and response data are available for 25 patients, who have completed at least the first cycle; 3 patients are currently receiving their first cycle of treatment. Grade 3-4 drug-related adverse events occurred in less than 15% of patients and included neutropenia (12%, 3 patients), anemia (12%, 3 patients), acute pulmonary edema (8%, 2 patients), pulmonary embolism (4%, 1 patient), creatinine increase (4%, 1 patient), nausea (4%, 1 patient), and fatigue (4%, 1 patient). No peripheral neuropathy was observed. Overall, the wCCd regimen was well tolerated, 3 patients (12%) required Carfilzomib dose reduction (grade 3 creatinine increase, grade 3 transaminase increase and grade 2 fever) and 3 patients (12%) required drug discontinuation due to adverse events (2 acute pulmonary edemas and 1 creatinine increase). Patients received a median of 5 cycles (range 1-9). After 4 induction cycles, 83% of patients achieved at least partial response, 39% at least very good partial response, and 22% complete response. Responses improved over time, as shown in table 1. During the study, only 2 patients progressed and 1 patient died, due to acute pulmonary edema considered probably related to treatment. Conclusions This is the first prospective study evaluating once weekly carfilzomib in treatment-naïve MM. wCCd therapy appears safe and effective in newly diagnosed MM patients. Responses became deeper with subsequent cycles and toxicities were manageable. The response rate observed with weekly carfilzomib compares favorably with similar studies with standard twice weekly carfilzomib infusion. Updated results will be presented at the meeting. Table 1 2nd cycle 4th cycle 6th cycle Complete Response 5% 22% 27% At least Very Good Partial Response 9% 39% 63% At least Partial Response 73% 83% 91% Disclosures Palumbo: Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Array BioPharma: Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Honoraria; Genmab A/S: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Off Label Use: Use off-label of Carfilzomib (proteasome inhibitor).. Bringhen:Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Janssen and Cilag: Honoraria; Celgene: Honoraria; Onyx: Consultancy. Larocca:Janssen Cilag: Honoraria; Celgene: Honoraria. Cavallo:Onyx: Honoraria; Janssen-Cilag: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Sanofi: 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; Janssen-Cilag: 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. Gaidano:Onyx: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Sonneveld:Millenium: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

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