A Phase I Safety Study of Enzastaurin Plus Bortezomib in the Treatment of Relapsed or Refractory Multiple Myeloma.

Abstract Abstract 1870 Poster Board I-895 Background: Enzastaurin is an oral serine/threonine kinase inhibitor that targets the PKC and PI3K/AKT pathways. Enzastaurin has demonstrated activity in preclinical models of multiple myeloma (MM), and clinical studies suggest activity and a favorable safety profile in a variety of hematological cancers. Enzastaurin has also demonstrated in-vitro synergy with bortezomib. Objectives: This phase I, open-label, multicenter, dose-escalation study was initiated to identify the recommended doses of enzastaurin and bortezomib in combination for phase II studies in patients (pts) with previously treated MM. Secondary objectives included evaluations of safety and response. Patients and Methods: A conventional dose-escalation scheme was applied. In dose level 1, pts received enzastaurin as a loading dose of 500 mg (250 mg po BID) on day 1 followed by daily doses of 125 mg po BID plus bortezomib 1.0 mg/m2 IV on days 8, 11, 15, and 18 in cycle 1 and days 1, 4, 8, and 11 thereafter. In dose level 2, pts received the same enzastaurin dose but a higher bortezomib dose (1.3 mg/m2). In dose level 3, pts received enzastaurin as a loading dose of 1125 mg (375 mg po TID) on day 1 followed by daily doses of 250 mg po BID plus 1.3 mg/m2 bortezomib. All treated pts were evaluated for response using the International Uniform Response Criteria (IURC; Durie et al. 2006) and European Group for Blood and Bone Marrow Transplantation (EBMT) criteria (Blade et al. 1998). All adverse events (AEs) were graded according to Common Toxicity Criteria for Adverse Events (CTCAE) v3.0. Results: A total of 23 pts, 4 in dose level 1, 3 in dose level 2, and 16 in dose level 3, were enrolled in the study, which is now closed to enrollment. There were 8 women and 15 men, with a median age of 62 years (range, 37–78 years); 91% of the pts had an ECOG performance status of 1 or 0, and the median number of prior systemic therapies was 3 (range, 2–12), with 17 pts previously treated with bortezomib. The median number of cycles completed was 4 (range, 1–20). No dose-limiting toxicities (DLTs) were observed; thus, dose level 3 was the recommended phase II dose. The combination was well tolerated with few grade 3/4 AEs. CTCAE drug-related grade 3/4 laboratory toxicities included: thrombocytopenia in 5 (22%) pts, anemia in 2 (9%) pts, increased creatinine in 1 (4%) pt, and hyponatremia in 1 (4%) pt. Drug-related grade 3/4 non-laboratory toxicities included: sensory neuropathy, prolonged QTc interval, and renal/genitourinary in 1 (4%) pt each. Serious drug-related AEs were increased serum creatinine and renal tubular necrosis in 1 (4%) pt and thrombocytopenia in 1 (4%) pt. The thrombocytopenia was not considered a DLT as the baseline platelet count was low secondary to MM. Five (22%) pts were discontinued from the study due to drug-related toxicities: renal tubular necrosis (also a serious AE) in 1 (4%) pt, peripheral neuropathy in 2 (9%) pts, neuralgia in 1 (4%) pt, and pain in extremity in 1 (4%) pt. There were no deaths on therapy; 1 pt died within 30 days of treatment due to progressive disease. Of the 23 enrolled pts, objective responses based on IURC criteria included 1 (4%) pt with a very good partial response (dose level 1), 2 (9%) pts with a partial response (in dose levels 2 and 3), 9 (39%) pts with stable disease, and 3 (13%) pts with progressive disease; 2 pts had no post-baseline response assessment, and 6 pts had unconfirmed stable disease or progressive disease. Two (9%) pts had a minimal response based on EBMT criteria. Activity was seen in pts regardless of prior exposure to bortezomib. Conclusions: The recommended phase II dose in patients with MM is enzastaurin 250 mg po BID with a loading dose of 1125 mg (375 mg po TID) on day 1 plus 1.3 mg/m2 bortezomib on days 1, 4, 8, and 11 (days 8, 11, 15, and 18 in cycle 1 only). The combination was generally well tolerated, and responses were observed. Disclosures: Ghobrial: Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Research Funding; Celgene: Honoraria, Speakers Bureau. Munshi:Millenium: 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; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yuan:Eli Lilly and Company: Employment. Schlossman:Millenium: Speakers Bureau; Celgene: Speakers Bureau. Laubach:Novartis: Consultancy. Anderson:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Millenium: Consultancy, Honoraria, Research Funding. Lin:Eli Lilly and Company: Employment. Wooldridge:Eli Lilly and Company: Employment. Richardson:Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keryx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gentium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Download Full-text

Oxaliplatin, Fludarabine, Cytarabine, and Rituximab Combination Therapy Induces High Response Rates in Agressive Chronic Lymphocytic Leukemia (CLL) and Richter's Syndrome (RS).

Blood ◽

10.1182/blood.v114.22.3443.3443 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3443-3443 ◽

Cited By ~ 1

Author(s):

Apostolia-Maria Tsimberidou ◽

William Wierda ◽

William Plunkett ◽

Susan O'Brien ◽

Thomas J. Kipps ◽

...

Keyword(s):

Phase I ◽

Dose Level ◽

Phase Ii ◽

Research Funding ◽

Response Rates ◽

Off Label ◽

Level 3 ◽

Level 1 ◽

Grade 3 ◽

Level 2

Abstract Abstract 3443 Poster Board III-331 Introduction The first Phase I-II clinical trial of oxaliplatin, fluradabine, cytarabine (Ara-C), and rituximab (OFAR1) demonstrated significant activity in refractory CLL and RS (Tsimberidou et al, J Clin Oncol, 2008;26:196). To enhance the response rate and decrease myelosuppression, the dose of oxaliplatin was increased to 30mg daily, the dose of Ara-C was decreased to 0.5g/m2 daily and the optimal number of days of fluradabine and Ara-C administration was explored (OFAR2). Methods In a Phase I-II study of OFAR2, patients were treated with oxaliplatin 30mg/m2, D1-4; fludarabine 30mg/m2, Ara-C 0.5g/m2; rituximab 375mg/m2, D3; and pelfigrastim 6mg, D6. Fludarabine and Ara-C were given on D2-3 (dose level 1) D2-4 (dose level 2) or D2-5 (dose level 3); courses were repeated every 4 weeks. Patients received prophylaxis for tumor lysis, DNA viruses, and PCP. A “3+3” design was used and the planned number of patients in the Phase II was 90 (CLL, 60; RS, 30). Results Ninety-one patients (CLL, 67; RS, 24) have been treated to date: Phase I, 12 patients (by dose level: 1, n=3; 2, n=6; and 3, n=3). DLTs were noted in 2 of 3 patients on dose level 3 (G4 diarrhea, 1; G4 neutropenic sepsis, 1); thus, dose level 2 was the MTD. Seventy-nine patients (relapsed CLL, 58; RS, 19) have been treated in the Phase II portion of the study. Patient characteristics were as follows: age > 60 years, 65%; 17p deletion, 38%; 11q deletion, 13%; 13q deletion, 16%; trisomy 12, 21%; no findings, 12%; unmutated IgVH, 80%; ZAP70-positive, 75%; and CD38 ≥30%, 58%. Response in patients treated in the Phase II recommended dose is shown in Table (evaluable, 67). The overall response rates in patients with 17p and 11q deletions were 48% and 55%, respectively. The median survival duration was 21 months (CLL, 21 months; RS, 9.5 months). At 18 months, the survival rates in patients with 17p and 11q deletions were 66% and 76%, respectively. Twelve patients underwent stem cell transplantation after OFAR2 (as post-remission therapy, n=10; as salvage, n=2). Overall, 196 cycles were administered. Grade 3-4 neutropenia, thrombocytopenia, and anemia were noted in 63%, 72%, and 39% of patients and in 57%, 70%, and 25% of cycles and Grade 3-4 infections in 19% of patients. Conclusion Preliminary results demonstrated that OFAR2 induced response in 40% of patients with RS and 63% of patients with relapsed/refractory CLL. OFAR2 had antileukemic activity in patients with 17p deletion. Clinical outcomes appeared to be superior to those of OFAR1 in refractory CLL, whereas results of OFAR1 appeared to be superior to those of OFAR2 in RS. Accrual is ongoing. Disclosures Tsimberidou: ASCO: ASCO Career Development Award; Sanofi: Research Funding. Off Label Use: Oxaliplatin is used off-label. Wierda:Genentech: Honoraria; Bayer, Sanofi-Aventis, Abbott, GSK: Research Funding; GSK, Trubion, Ligand, Genentech, Medimmune, Abbot: Consultancy; Celgene: Speakers Bureau. Plunkett:Sanofi-Aventis: Research Funding. O'Brien:Genentech: Research Funding; Sanofi: Consultancy. Kipps:NCI: Grant P01CA-81534.

Download Full-text

The Combination Of Palbociclib Plus Bortezomib Is Safe and Active In Patients With Previously Treated Mantle Cell Lymphoma: Final Results Of a Phase I Trial

Blood ◽

10.1182/blood.v122.21.4393.4393 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4393-4393 ◽

Cited By ~ 4

Author(s):

Peter Martin ◽

Maurizio DiLiberto ◽

Christopher E Mason ◽

Scott A Ely ◽

Jia Ruan ◽

...

Keyword(s):

Cell Cycle ◽

Dose Level ◽

Research Funding ◽

Hematologic Toxicity ◽

Advisory Committees ◽

Level 3 ◽

Previously Treated ◽

Level 1 ◽

Grade 3 ◽

Dose Levels

Abstract Introduction Mantle cell lymphoma (MCL) is characterized by cell cycle dysregulation due to cyclin D1 and CDK4 overexpression. Palbociclib (PD 0332991) is an orally bioavailable, specific, reversible inhibitor of CDK4/6 that induces prolonged early G1 arrest (pG1) in MCL cells and durable remissions in patients with MCL. Moreover, we have evidence that palbociclib-induced pG1 sensitizes MCL cells to killing by bortezomib and that sensitization is amplified upon withdrawal of palbociclib, when MCL cells synchronously enter S phase (pG1-S). Targeting CDK4 in combination with bortezomib, therefore, is a rational and novel therapeutic combination. We report the final results of a phase I trial of palbociclib plus bortezomib in patients with previously treated MCL. Methods Adults with previously treated MCL and adequate bone marrow and organ function were received palbociclib orally at doses of 75 mg (dose level 1), 100 mg (dose level 2), or 125 mg (dose levels 3 and 4) for 12 days. Bortezomib was administered by IV or SC injection at 1 mg/m2 (dose levels 1-3) or 1.3 mg/m2 (dose level 4) on days 8, 11, 15, and 18 of each 21-day cycle. Subjects underwent core needle biopsies of tumor tissue pre-treatment, on day 8 (in pG1) and on day 21 (in pG1-S phase) of cycle 1. Subjects were restaged following cycles 2, 5, and 8 and then every 4 cycles. Subjects could remain on the study regimen until progression, unacceptable toxicity, or withdrawal. Dose levels were escalated according to the standard 3+3 schema. Dose limiting toxicity (DLT) was defined as treatment-related grade 3-4 toxicity occurring during cycle 1 or a delay in cycle 2 of > 1 week due to treatment-related grade 4 neutropenia or thrombocytopenia. The primary objective was to estimate the maximum tolerated dose of the combination. Secondary objectives included response rate, duration of response, and evaluation of the pharmacokinetic and pharmacodynamic profiles at multiple time points and across all dose levels. Results Nineteen subjects were enrolled: 6 in dose level 1, 3 in dose level 2, 7 in dose level 3, and 3 in dose level 4. The median age was 64 years (range 42-81). The median number of prior therapies was 3 (range 1-7). The number of subjects with low, intermediate, and high-risk MIPI scores was 6, 11, and 2, respectively. Two subjects experienced DLT: thrombocytopenia (level 1), neutropenia (level 3). Grade 3-4 hematologic toxicity included neutropenia (63%), thrombocytopenia (53%), lymphopenia (32%), and anemia (11%). Treatment-related grade 3-4 non-hematologic toxicity included zoster (1). Grade 1-2 toxicities occurring in >2 pt included: fatigue (47%), pain (42%), bleeding/bruising (37%), increased creatinine (26%), constipation (26%), rash (21%), nausea/vomiting (21%), sensory neuropathy (21%), dyspnea (21%), hypoalbuminemia (16%), cough (16%), edema (16%), infection (16%), increased AST (16%), hypocalcemia (16%), increased alk phos (16%). Reasons for ultimately stopping treatment include: progression (9), toxicity (6), and non-compliance (1). All 3 patients at dose level 4 required dose delays/reductions during cycle 2 due to toxicity. There appeared to be an association with dose of palbociclib and response, with one responder at each of dose levels 1 and 2, and 4 patients remaining free from progression for 1 year at dose level 3, including one complete response. Only one responding patient progressed on therapy. All patients with serial biopsies achieved pG1 on day 8, with reduction in CDK4/CDK6-specific Rb phosphorylation and Ki67 by immunohistochemistry. The primary MCL tumor cells express cell cycle genes scheduled for early G1 such as cyclin D1 and CDK4, but not genes programmed for other phases of the cell cycle such MKi67, E3F3, CDK1, CCNA2, as determined by RNA-seq. Conclusion Daily palbociclib 125 mg for 12 days can be safely combined with bortezomib 1 mg/m2 twice weekly, while higher doses were limited by myelosuppression. The combination induced durable responses in some patients. Palbociclib induced pG1, even at the lowest dose. However, the initial cell cycle control by palbociclib did not predict clinical response. Rather, pG1 appears to induce an imbalance in gene expression that is associated with response to the combination of palbociclib plus bortezomib. Strategies to control the cell cycle and dissect the underpinning mechanisms appear promising in MCL and warrant further evaluation. Disclosures: Martin: Teva: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Speakers Bureau; Millennium: Research Funding; Seattle Genetics: Consultancy, Speakers Bureau. Ruan:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Seattle Genetics, Inc.: Membership on an entity’s Board of Directors or advisory committees. Leonard:Millennium: Consultancy.

Download Full-text

Vorinostat in Combination with Pegylated Liposomal Doxorubicin (PLD) and Bortezomib (B) in Patients with Relapsed/Refractory Multiple Myeloma (R/R MM): Final Results of a Phase I Study,

Blood ◽

10.1182/blood.v118.21.3985.3985 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3985-3985

Author(s):

Peter M. Voorhees ◽

Cristina Gasparetto ◽

Keren Osman ◽

Kristy L. Richards ◽

Madlyn Ferraro ◽

...

Keyword(s):

Board Of Directors ◽

Dose Level ◽

Research Funding ◽

Phase I Study ◽

Systolic Dysfunction ◽

Median Number ◽

Refractory Disease ◽

Advisory Committees ◽

Level 3 ◽

Grade 3

Abstract Abstract 3985 Introduction: Although the combination of PLD and B improved time to progression (TTP) compared with B alone in patients (pts) with R/R MM, the overall response rate (ORR) of the regimen was only 44%, while TTP was 9.3 months. As such, strategies that build upon the efficacy of this regimen are needed. Vorinostat (V) is a histone deacetylase inhibitor that has demonstrated additive to synergistic activity with proteasome inhibitors and anthracyclines in preclinical models of MM. We therefore conducted a phase I study evaluating the safety and preliminary efficacy of V when combined with the PLD/B backbone. Patients and Methods: Pts were treated with standard doses of B and PLD (B 1.3mg/m2 on D1, 4, 8, 11, and PLD 30mg/m2 on D4) and escalating doses of V from either D4-11 or D1-14 of a 3-week cycle. Dose escalation followed a standard 3 + 3 design. Eligibility criteria included a diagnosis of relapsed or relapsed/refractory MM, absolute neutrophil count ≥1.0×109/L, platelets ≥100×109/L, creatinine clearance ≥30mL/min, and adequate hepatic and cardiac function. The primary objective was to determine the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the regimen and the secondary objective was to assess preliminary efficacy. Results: 32 pts were enrolled at the following dose levels: The median age was 61 (39–75) and median β2-microglobulin 3.57 mcg/mL (1.26–10.6). 69% of the pts were male, 31% female. The median time from diagnosis was 46 months (13–155) and median number of prior lines of therapy 2 (1–9). 78% of pts had received prior B, 56% PLD or doxorubicin, 91% thalidomide and/or lenalidomide, and 66% autologous and/or allogeneic stem cell transplantation. 44% (11 of 25 pts) had disease refractory to prior B-based therapy. The median number of complete cycles administered was 6 (0–15). No patients on dose level 1 or 2 suffered DLTs. One of 6 pts on dose level 3 had a DLT consisting of grade 4 systolic dysfunction in the setting of atrial flutter, which subsequently resolved. Two of 6 pts at dose level 4 experienced grade 4 thrombocytopenia in cycle 1, establishing dose level 3 as the MTD. Nine pts experienced serious adverse events at least possibly attributable to protocol therapy, including the 1 case of systolic dysfunction/atrial flutter noted above, 2 cases of nausea and vomiting with dehydration, and diarrhea, diastolic dysfunction, upper respiratory infection, syncopal episode and hypertension in 1 pt each. Grade 3 neutropenia was seen in 34% of pts (3% grade 4). 4 pts had grade 3 infections (1 attributed to protocol therapy), but no grade 4 infections were seen regardless of attribution. Grade 3 and 4 thrombocytopenia was documented in 16% and 34%, but no serious hemorrhagic events were seen. Non-hematologic toxicity at least possibly attributable to therapy included fatigue in 63% (16% grade 3, 0% grade 4). GI toxicity was common with anorexia, constipation, diarrhea, nausea and vomiting occurring in 47% (3% grade 3), 50%, 81% (16% grade 3, 3% grade 4), 78% (9% grade 3) and 50% (9% grade 3) of pts, respectively. Peripheral neuropathy at least possibly attributable to therapy was seen in 38% of pts (6% grade 3), while hand-foot syndrome was seen in 25% (9% grade 3). There were no deaths on study. Among 31 evaluable pts, the ORR using International Uniform criteria was 65% (95% confidence interval (CI): 45–81%), and the ≥very good partial remission (VGPR) rate was 29% (95% CI: 14–48%). The ORR + minimal response (MR) rate was 74% (95% CI: 55–88%). Of 14 pts with B-sensitive disease, there was 1 MR, 5 PRs and 5 VGPRs. Two PRs, 2 VGPRs and 1 complete remission (CR) were documented in 6 pts with B-naïve disease. Notably, there were 2 MRs, 4 PRs and 1 CR out of the 11 pts with B-refractory disease. Conclusions: The MTD of vorinostat when added to the PLD/bortezomib backbone is 400 mg administered daily on days 4–11. The ORR is highly promising, with responses seen in pts with bortezomib-naïve, -sensitive and -refractory disease. Although serious toxicities were infrequent, constitutional and GI side effects were highly prevalent. All together, our data support further development of this combination in pts with MM, with special attention to developing strategies and guidelines to better ameliorate toxicity. Disclosures: Voorhees: Merck: Research Funding; Celgene: Research Funding; Centocor Ortho Biotech: Research Funding; MedImmune: Consultancy; Pfizer: Research Funding. Off Label Use: Vorinostat for the treatment of relapsed and relapsed and refractory multiple myeloma. Gasparetto:Millennium Pharmaceuticals: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees. Richards:Merck: Consultancy. Garcia:Millennium Pharmaceuticals: Speakers Bureau; Sigma-Tau: Speakers Bureau. MacLean:Novartis: Speakers Bureau. Orlowski:Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Honoraria; Johnson and Johnson: Research Funding.

Download Full-text

Phase I Trial of Systemic Administration of Vesicular Stomatitis Virus Genetically Engineered to Express NIS and Human Interferon, in Patients with Relapsed or Refractory Multiple Myeloma (MM), Acute Myeloid Leukemia (AML), and T-Cell Neoplasms (TCL)

Blood ◽

10.1182/blood-2018-99-119444 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3268-3268

Author(s):

Martha Q. Lacy ◽

Kah-Whye Peng ◽

Stephen J. Russell ◽

Amylou C. Dueck ◽

Mrinal M. Patnaik ◽

...

Keyword(s):

Phase I ◽

Board Of Directors ◽

Dose Level ◽

Research Funding ◽

Tumor Burden ◽

Advisory Committees ◽

Equity Ownership ◽

Level 1 ◽

Grade 3 ◽

Level 2

Abstract Background: We previously reported successful treatment of myeloma with an oncolytic virus, MMV-NIS. Preexisting immunity against measles made use of that virus unsatisfactory. The Indiana strain of Vesicular Stomatitis Viruses (VSV) are being developed as anticancer drugs for the treatment of a variety of malignancies. To ensure tumor selective replication and spread, we designed the VSV to encode interferon beta. Expression of IFNβ also serves as a STING agonist to activate host immunity against the cancer. The sodium iodide symporter (NIS) is inserted as a reporter gene into the viral genome to enable noninvasive monitoring of viral spread using PET/CT imaging. We report a Phase I clinical trial of intravenous administration of VSV-IFNβ-NIS for relapsed hematological malignancies including MM, AML, and TCL. Methods: Arm A consisted of patients with low tumor burden. Arm B included patients with high tumor burden. Both arms consisted of a classical 3+3 phase I trial, starting at 5x10^9 TCID50 (dose level 1) through 5x10^11 TCID50 (dose level 4), given as a single IV dose. In order to obviate potential toxicity from high interferon levels, Arm B received ruxolitinib 15 mg twice daily for 10 days beginning on day -1. The primary objective was determining the maximum tolerated dose (MTD) of VSV-IFNβ-NIS alone and in combination with ruxolitinib; secondary objectives include estimating the safety profile and preliminary efficacy. Correlative objectives include monitoring the pharmacodynamics of viral replication through SPECT/CT imaging with NIS gene, viremia, virus shedding, changes in the immune profile of peripheral blood leukocytes, and immunohistochemistry for immune cell infiltrates in tumors. Adverse events (AEs) are reported herein based on CTCAE v4 with the exception of cytokine release syndrome (CRS) which is based on Lee (Blood 2014; 124(2):188-195) criteria. Results: To date, 10 patients have received IV VSV-IFNβ-NIS; 8 in Arm A and 2 in Arm B. In Arm A, 3 patients were treated at dose level 1, 3 at dose level 2 and 2 at dose level 3. At dose level 1, there were three grade 3 hematologic AEs (neutropenia [1], lymphopenia [2]), and no grade 3+ non-hematologic AEs. At dose level 2, there were two grade 3 hematologic AEs (anemia [1], lymphopenia [1]), and two grade 3 non-hematologic AEs (nausea [1], dehydration [1]). A grade 2 CRS by Lee criteria was also observed. At dose level 3, 2 patients have been enrolled and data are maturing for DLT evaluation. In Arm B (VSV + rux), 2 patients have been enrolled and data are maturing for dose limiting toxicity (DLT) evaluation. Other grade 1 and 2 toxicities have included fever, hypertension, headache, electrolyte abnormalities, nausea, vomiting, transient elevation of liver function tests and creatinine. All grade 1 and 2 toxicities resolved within 72 hours. Among the 6 patients evaluable for response, there was one partial remission (TCL patient treated at dose level 2), and 5 with progressive disease. Multiple cytokines increased at 4h post infusion of virus, but most returned to baseline levels by 24h.Viremia was detectable in all patients at the end of infusion, and to varying levels at 30 mins, 1, 2, 4, 24, 48h or 72 hours post virus infusion. No persistent viremia was observed. No infectious virus was recovered in buccal swabs or urine and neutralizing anti-VSV antibodies were present by day 29. Extensive immune phenotyping and ELIspot assays for shared antigens are ongoing. Conclusion: In the lowest dose levels tested to date, VSV-IFNβ-NIS has not led to any observed dose limiting toxicity. Dose escalation is ongoing and updated results will be reported. Disclosures Lacy: Celgene: Research Funding. Peng:Vyriad: Equity Ownership. Russell:Vyriad: Equity Ownership. Dueck:Bayer: Employment; Phytogine: Employment; Pfizer: Honoraria. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:spectrum: Consultancy, Honoraria; Physicians Education Resource: Consultancy; Ionis: Honoraria; janssen: Consultancy; Medscape: Consultancy; celgene: Consultancy; Apellis: Consultancy; Prothena: Honoraria; Amgen: Consultancy; annexon: Consultancy; Abbvie: Consultancy; Research to Practice: Consultancy; Teva: Consultancy; Alnylam: Honoraria. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Al-Kali:Novartis: Research Funding. Naik:Vyriad: Equity Ownership. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

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

Blood ◽

10.1182/blood-2020-139174 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-40

Author(s):

Hang Quach ◽

Simon J Harrison ◽

Je-Jung Lee ◽

Nichloas Murphy ◽

Jae Hoon Lee ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Board Of Directors ◽

Phase Ii ◽

Primary Endpoint ◽

Research Funding ◽

Open Label ◽

Advisory Committees ◽

Open Label Phase ◽

Grade 3

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

Download Full-text

Phase I-II Study of Clofarabine-Melphalan-Alemtuzumab (CMA) Conditioning for Allogeneic Hematopoietic Cell Transplantation (HCT) in Patients with Advanced Hematologic Malignancies: Determination of MTD and Outcomes.

Blood ◽

10.1182/blood.v114.22.197.197 ◽

2009 ◽

Vol 114 (22) ◽

pp. 197-197 ◽

Cited By ~ 1

Author(s):

Koen van Besien ◽

Justin Kline ◽

Lucy A Godley ◽

Richard A. Larson ◽

Vu H. Nguyen ◽

...

Keyword(s):

Phase I ◽

Board Of Directors ◽

Dose Level ◽

Phase Ii ◽

Renal Toxicity ◽

Phase Ii Study ◽

Hematologic Malignancies ◽

Advisory Committees ◽

Grade 3 ◽

One Year

Abstract Abstract 197 Supported by an unrestricted grant from Genzyme Corporation. Fludarabine (Flu) melphalan-alemtuzumab is a well tolerated, reduced intensity conditioning regimen for HCT. Clofarabine (Clo), a second generation nucleoside analog with excellent activity in acute leukemia, might enhance disease control over Flu. We report outcomes of a completed phase I and ongoing phase II study of CMA conditioning for allogeneic peripheral blood HCT. Tacrolimus was administered as GVHD prophylaxis. For the phase I cohort, one pt was enrolled per dose level, until the first DLT or until 2 had grade 3 toxicity. Dose level 1 consisted of: clo 10 mg/m2/day on d −7 to −3 and melphalan 100 mg/m2 on day −2. Clo was increased by 10 mg/m2/day per cohort until 40 mg/m2/day. Then, melphalan was increased by 20 mg/m2 until 140 mg/m2. Alemtuzumab was given at a fixed dose of 20 mg/day on d −7 to −3. Twelve pts were accrued in the phase I portion of whom three remain in remission at 26, 22 and 21 months. Forty pts, median age 53 (24–69), have been accrued in the phase II study of whom 16 had related and 24 unrelated donors. 20 had AML/MDS (6 refractory, 4 CR2, 9 CR1, 1 untreated MDS), 16 NHL (6 refractory, 9 chemosensitive relapse, 1 CR1) 2 CLL, 2 MPD. ASBMT risk score was high in 14, intermediate in 14, and low in 12. Performance score was 0 in 19, 1 in 17, 2 in 2, and not documented in 2 patients. The phase II dose was initiated at Clo 40 mg/m2/day x 5 days and melphalan 140 mg/m2. Twenty-four pts received this dose. Grade 3 renal toxicity occurred between day −7 and day +7 in 4 of 24 (17%) pts receiving this dose. The phase II dose was then reduced to Clo 30 mg/m2/day x 5 days and melphalan 140 mg/m2, and used to treat 16 pts. One pt with preexisting cardiomyopathy and refractory AML died during conditioning from cardiovascular failure. No grade 3 renal toxicity has been observed in this cohort and 3 pts had reversible grade 2 renal failure. Other toxicities included: gr 2–3 reversible ALT elevation between day −2 and day +5 in 8 pts; gr 2 reversible bilirubin elevation in 1 pt. No grade 3–4 hand foot syndrome or VOD occurred in this cohort. All evaluable pts engrafted. Twenty of 24 pts had full donor CD3 chimerism on day 30 and 2 had mixed donor chimerism. 11 pts had gr II aGVHD, and 3 had gr IIII/IV aGVHD. 7 have cGVHD.With a median follow-up of 313 days (19–607), 24 of 40 pts (60%) in the phase II portion of the study remain in remission. Eight have relapsed, 4 of whom have died. Eight others have died of treatment-related causes (7 after Clo 40 and 1 after Clo 30). Estimated one year survival is 72% (95%CI, 56–88) and PFS is 63% (45–81%). Neither dose of Clo (40 vs 30), donor type (MUD vs related), age (< 50 vs >50) affected outcomes. One year PFS was 56% (28–84) for NHL and 68% (46–90) for AML/MDS (P=NS). One year PFS was 43% (15–71%) for ASBMT high risk pts vs 70% (50–90%) for ASBMT low/intermediate risk pts (P=0.01; Figure 1). Conclusions: Clofarabine - melphalan - alemtuzumab conditioning induces durable remissions in a substantial fraction of patients with advanced hematologic malignancies. Clo 30/Mel 140 has an excellent safety profile. Disclosures: Off Label Use: clofarabine for transplant conditioning. Kline:Genzyme corporation: Membership on an entity's Board of Directors or advisory committees. Odenike:Genzyme corporation: Membership on an entity's Board of Directors or advisory committees. Stock:Genzyme: Research Funding.

Download Full-text

A Phase I Study of Bendamustine Combined with Lenalidomide and Dexamethasone in Patients with Refractory or Relapsed Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.1856.1856 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1856-1856 ◽

Cited By ~ 1

Author(s):

Suzanne Lentzsch ◽

Amy O’Sullivan ◽

Silvana Lalo ◽

Carrie Kruppa ◽

Diane Gardner ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Board Of Directors ◽

Dose Level ◽

Research Funding ◽

Advisory Board ◽

Clinical Activity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 1856 Poster Board I-882 Background: Lenalidomide is an analog of thalidomide that has shown significant clinical activity in patients with relapsed or refractory multiple myeloma (MM), both as a single agent and in combination with dexamethasone. Bendamustine is a bifunctional alkylating agent that is approved for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma that has progressed during or relapsed within 6 months following a rituximab-containing regimen. Bendamustine combined with lenalidomide may be an effective treatment option for MM patients, particularly those with preexisting or bortezomib-induced neuropathy. Our primary objective was to determine the maximum tolerated dose (MTD) and safety profile of bendamustine and lenalidomide when administered with dexamethasone for patients with relapsed or refractory MM. Methods: Patients aged ≥18 years with confirmed, measurable stage 2 or 3 MM that was refractory to or progressed after 1 or more prior therapies, including lenalidomide, received bendamustine by intravenous infusion on days 1 and 2, oral lenalidomide on days 1–21, and oral dexamethasone on days 1, 8, 15, and 22 of each 28-day cycle. Treatment was continued until a plateau of best response, as determined by the IBMTR/ABMTR, was reached. Study drug doses were escalated through 4 levels (Table), with 3–6 patients enrolled at each level depending on the rate of dose-limiting toxicity (DLT). After determining the MTD, up to an additional 12 patients will be enrolled in an MTD expansion arm to better evaluate toxicity and clinical activity. Secondary endpoints included preliminary efficacy, as evidenced by objective response, time to disease progression, and overall survival. Results: To date, 11 patients have been enrolled, with a median age of 63 years (range, 38–75 years). The MTD of bendamustine and lenalidomide has not been identified at this point; currently, patients are enrolling on dose level 3 with 100 mg/m2 bendamustine and 10 mg lenalidomide. Thus far, DLT included 1 grade 4 neutropenia at dose level 2. Nine of 11 patients are currently eligible for response assessment. A partial response was observed in 67% of patients, including 1 very good partial response and 5 partial responses (PR). Two patients experienced stable disease and 1 exhibited progressive disease. Grade 3/4 adverse events included grade 3 neutropenia, thrombocytopenia, anemia, hyperglycemia, and prolonged QTC, and 1 grade 4 neutropenia. Conclusions: Bendamustine, lenalidomide, and dexamethasone form a well-tolerated and highly active regimen even in heavily pretreated MM patients, with a PR rate of 67%. Additional updates on response and MTD will be available at the time of presentation. Disclosures: Lentzsch: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Consultancy, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Bendamustine is not FDA approved for the treatment of multiple myeloma in the USA. Burt:Millennium: Honoraria; Celgene: Honoraria. Mapara:Resolvyx: Consultancy, Research Funding; Genzyme: Membership on an entity's Board of Directors or advisory committees; Gentium: Equity Ownership; Celgene: Spouse is consultant , has received research funding, and participates on advisory board; Cephalon: Spouse has received funding for clinical trial and participates on advisory board. Redner:Biogen: Equity Ownership; Wyeth: Equity Ownership; Glaxo-Smith-Kline: Equity Ownership; Pfizer: Equity Ownership; Genzyme: Membership on an entity's Board of Directors or advisory committees. Roodman:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy; Acceleron: Consultancy. Zonder:Amgen: Consultancy; Pfizer: Consultancy; Cephalon: Consultancy; Millennium: Consultancy, Speaking (CME only); no promotional talks.

Download Full-text

Pomalidomide, Cyclophosphamide, and Dexamethasone Is Superior to Pomalidomide and Dexamethasone in Relapsed and Refractory Myeloma: Results of a Multicenter Randomized Phase II Study

Blood ◽

10.1182/blood.v124.21.303.303 ◽

2014 ◽

Vol 124 (21) ◽

pp. 303-303 ◽

Cited By ~ 6

Author(s):

Rachid Baz ◽

Thomas G. Martin ◽

Melissa Alsina ◽

Kenneth H. Shain ◽

Hearn J. Cho ◽

...

Keyword(s):

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Advisory Committees ◽

Overall Response ◽

Best Response ◽

Randomized Phase Ii ◽

Grade 3

Abstract Background: Pomalidomide-dexamethasone results in an overall response rate of 33% and median PFS of 4.2 months in patients with prior lenalidomide and bortezomib (Richardson et al. Blood 2014). In this randomized phase II trial, we compared pomalidomide-dexamethasone (arm B) versus the addition of oral weekly cyclophosphamide to pomalidomide-dexamethasone (arm C) in patients with lenalidomide-refractory multiple myeloma (MM). We have previously reported that the recommended phase II dose of cyclophosphamide with standard-dose pomalidomide + dexamethasone was 400 mg PO D1, 8, 15. Patients and Methods: Eligible patients had relapsed and refractory MM after at least 2 prior therapies and were lenalidomide refractory. Patients had a platelet count ≥ 50,000/mm3 and ANC ≥ 1,000/mm3 (patients with ≥50% bone marrow plasmacytosis were allowed if platelet count was ≥ 30,000/mm3and ANC could be supported with GCSF during screening and therapy). Patients were randomized (1:1) to receive pomalidomide 4 mg PO D1-21 and dexamethasone 40 mg PO D1, 8, 15, 22 (20 mg if older than 75 years) (arm B) with or without oral cyclophosphamide 400 mg PO D1, 8, 15 of a 28-day cycle (arm C). Patients randomized to arm B were allowed to cross over to arm C in the event of disease progression. Thromboprophylaxis was mandated with aspirin, warfarin, or LMWH. The primary endpoint was overall response rate using IMWG criteria. Secondary endpoints included an evaluation of PFS, OS and safety of the two arms. Results: Between 7/2012 and 3/2014, 36 patients were randomized to arm B and 34 to arm C. Patients characteristics were not different between the 2 arms (table below). The median number of prior therapies was 4 (2-12). All patients were lenalidomide refractory and none received prior pomalidomide. After a median follow up of 15 months, the overall response rate (partial response or better) was 39% and 65% (p=0.03) for arm B and C, respectively. The clinical benefit rate (minimal response or better) was 64% and 79% (p=0.2) for arm B and C, respectively. The median PFS was 4.4 months (95% CI 2.3-5.9) for arm B and 9.2 months (95% CI 4.6-16) for arm C (log rank p=0.04). As of July 2014, 28 patients had died (16 arm B, 12 arm C) with median overall survival of 10.5 versus 16.4 months (p=0.08) for arm B and C, respectively. Hematologic grade 3/4 adverse events were more frequent in arm C, although this was not statistically significant (see table). Thirteen patients crossed over and oral weekly cyclophosphamide was added to their tolerated dose of pomalidomide dexamethasone. For those patients, the best response was as follows: 2 PR, 2 MR, and 6 SD, 3 PD. Conclusions: Pomalidomide-dexamethasone in combination with oral weekly cyclophosphamide resulted in a superior response rate and PFS compared to pomalidomide-dexamethasone alone in patients with relapsed and refractory MM. The increased hematologic toxicities, as a result of the addition of oral cyclophosphamide, were manageable. Table Arm B (N=36) Arm C (N=34) P value Age, years, median (range) 63 (50-78) 64 (47-80) 0.7 Male, n (%) 23 (64) 18 (53) 0.3 Number of prior therapies, median (range) 4 (2-12) 4 (2-9) 0.5 Bortezomib refractory, n (%) 28 (78) 24 (71) 0.3 Carfilzomib refractory, n (%) 16 (44) 13 (38) 0.5 Prior high-dose therapy, n (%) 27 (75) 28 (82) 0.6 Prior alkylating agent, n (%) 32 (89) 32 (94) 1 B2-microglobulin, median (range) 3.2 (1.6-10) 3.6 (1.5-13.9) 0.5 Serum creatinine, median (range) 1 (0.5-2.3) 0.9 (0.6-2.1) 0.6 High-risk cytogenetics, n (%) 5 (24) 6 (28) 0.8 Deletion 17p, n (%) 3 (14) 4 (20) 0.8 t(4;14), n (%) 3 (14) 3 (14) 0.9 Trisomy or tetrasomy 1q, n (%) 11 (55) 6 (33) 0.4 Best response (partial response or better), n (%) 14 (39) 22 (65) 0.03 Clinical benefit rate (MR or better), n (%) 23 (64) 27 (79) 0.2 Grade 3/4 neutropenia, n (%) 12 (33) 17 (50) 0.2 Grade 3/4 febrile neutropenia, n (%) 4 (11) 6 (18) 0.5 Grade 3/4 thrombocytopenia, n (%) 2 (5) 5 (15) 0.2 Grade 3/4 anemia, n (%) 3 (8) 7 (20) 0.2 Grade 3/4 pneumonia, n (%) 4 (11) 3 (9) 1 Grade 3/4 fatigue, n (%) 2 (5) 4 (12) 0.4 Number of serious adverse events 17 20 Disclosures Baz: Celgene: Research Funding; Millenium: Research Funding; Bristol-Myers Squibb: Research Funding; Karypharm: Research Funding; Sanofi: Research Funding. Off Label Use: Pomalidomide cyclophosphamide dexamethasone in relapsed refractory myeloma. Martin:Sanofi: Research Funding; Novartis: Speakers Bureau. Alsina:Triphase: Research Funding; Millenium: Research Funding. Shain:Onyx / Amgen: Research Funding; Treshold: Research Funding. Chari:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Membership on an entity's Board of Directors or advisory committees. Jagannath:Celgene: Honoraria; Millennium: Honoraria; Sanofi: Honoraria.

Download Full-text

Phase II Randomized, Multicenter Study of Lenalidomide Vs Best Investigator’s Choice in Relapsed/Refractory Mantle Cell Lymphoma: Results of the MCL-002 (SPRINT) Study

Blood ◽

10.1182/blood.v124.21.626.626 ◽

2014 ◽

Vol 124 (21) ◽

pp. 626-626 ◽

Cited By ~ 6

Author(s):

Marek Trneny ◽

Thierry Lamy ◽

Jan Walewski ◽

Wojciech Jurczak ◽

David Belada ◽

...

Keyword(s):

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Cell Lymphoma ◽

Tumor Burden ◽

Advisory Committees ◽

First Response ◽

Mantle Cell ◽

Grade 3 ◽

Prognostic Profile

Abstract Introduction: Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin’s lymphoma with poor outcome, especially after failure of first-line treatment. Lenalidomide, an immunomodulatory drug with antineoplastic and antiproliferative effects, has shown activity in single-arm phase II studies of patients with relapsed/refractory (R/R) MCL. The present controlled randomized study compared the efficacy and safety of lenalidomide vs investigator’s choice (IC) in patients with R/R MCL. Methods: MCL-002 (SPRINT), a European multicenter, open-label, phase II study enrolled patients with up to 3 relapses or who failed prior therapy and were ineligible for intensified treatment or stem cell transplantation (NCT00875667). Oral lenalidomide was given at 25 mg/day on days 1-21 of each 28-day cycle until progressive disease (PD) or intolerability. The IC treatment consisted of single-agent therapy with cytarabine, rituximab, gemcitabine, fludarabine, or chlorambucil. Patients who progressed on IC per investigator judgment were allowed to crossover to lenalidomide. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), time to first response, duration of response (DOR), overall survival (OS), and safety. Response assessments were centrally reviewed using the modified IWG criteria. Results: 254 patients with R/R MCL were randomized 2:1 to lenalidomide (n=170) or IC (n=84). Patients had median age 68.5 years, were predominantly male (73%), and had received a median of 2 prior therapies. 91% had stage III/IV disease at diagnosis, with 34% high-risk MIPI, 43% high tumor burden, and 20% bulky disease at baseline. Overall, patients on the lenalidomide arm had a worse prognostic profile than the IC arm due to higher tumor burden and disease risk (>5 percentage points for a number of parameters). After a median time of 2.9 months, 39 patients (46%) from the IC arm crossed over to lenalidomide due to PD. Overall, 84 patients remain on lenalidomide (15 having crossed over from IC) and 11 patients on IC without PD. At a median follow-up time on study of 15.9 months, the risk reduction for PFS was 39% (HR=0.61 [95% CI, 0.44-0.84]; P=0.004; Table) in favor of lenalidomide (median PFS: 8.7 months lenalidomide vs 5.2 months IC). ORR was significantly improved for lenalidomide vs IC (40% vs 11%; CR/CRu 5% vs 0%). Median time to first response was 4.3 months for lenalidomide (not reached for IC). Median DOR (16.1 vs 10.4 months) and OS on mature data (27.9 vs 21.2 months) were longer for lenalidomide vs IC. Efficacy results were consistent among subgroups. Safety data in 250 patients receiving ≥1 dose showed more dose reductions in lenalidomide-treated patients (41%) vs IC (17%), due in part to a longer median duration of lenalidomide treatment vs IC, and to strict dose modification rules for lenalidomide. The most common grade 3/4 adverse events (AEs) were neutropenia (lenalidomide 44% vs IC 34% [without increased risk of infection]), thrombocytopenia (18% vs 28%), and leukopenia (8% vs 11%). Tumor flare reaction occurred in lenalidomide patients only (10%; 2% grade ≥3); 1 patient in each arm experienced tumor lysis syndrome. Invasive second primary malignancies were identified in 4% and 5% of lenalidomide and IC treated patients, respectively. Conclusions: The MCL-002 study demonstrated a statistically significant and clinically meaningful improvement in PFS for lenalidomide over best IC monotherapy in patients with advanced R/R MCL despite a worse prognostic profile in the lenalidomide arm at baseline. In addition, ORR and CR rates, TTR, DOR, and OS were improved for lenalidomide over IC. The DOR has been remarkably consistent in various studies with lenalidomide in MCL patients. The safety profile for lenalidomide was as expected and no new safety signals were identified. The results of this first randomized, controlled study of lenalidomide showed superior efficacy compared to IC in patients with R/R MCL with a manageable toxicity profile. Table Efficacy of lenalidomide vs IC in R/R MCL Efficacy Lenalidomide (n=170) IC (n=84) P PFS (Lenalidomide vs IC) Median PFS, mo (95% CI) 8.7 (5.54-12.14) 5.2 (3.67-6.95) Sequential HR (95% CI) 0.61 (0.44-0.84) Sequential log-rank test p-value 0.004 ORR, n (%) 68 (40) 9 (11) <0.001 CR/CRu, n (%) 8 (5) 0 (0) 0.043 Median DOR, mo 16.1 10.4 0.421 Median OS, mo 27.9 21.2 0.52 Disclosures Trneny: Celgene, Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Walewski:Celgene: Consultancy, Other, Research Funding; Janssen-Cilag: Consultancy; Mundipharma : Consultancy, Research Funding; Roche: Consultancy, Honoraria, Other, Research Funding. Jurczak:Celgene, Eisai, Gilead, Janssen, Pharmacyclics, Pfizer, Roche, Novartis, Spectrum, Takeda, Teva: Research Funding. Belada:Celgene: Research Funding. Mayer:Janssen Research & Development: Research Funding; Roche: Research Funding; GlaxoSmithKline: Research Funding; Celgene: Research Funding. Biyukov:Celgene: Employment. Patturajan:Celgene: Employment. Casadebaig Bravo:Celgene: Employment. Arcaini:Celgene, Roche, Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

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

Blood ◽

10.1182/blood-2018-99-114125 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 354-354 ◽

Cited By ~ 7

Author(s):

Raajit K. Rampal ◽

Srdan Verstovsek ◽

Sean M Devlin ◽

Eytan M. Stein ◽

Tapan M. Kadia ◽

...

Keyword(s):

Platelet Count ◽

Combination Therapy ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Single Agent ◽

Response Assessment ◽

Platelet Response ◽

Advisory Committees ◽

Grade 3

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

Download Full-text