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 ◽  
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.

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

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1870-1870
Author(s):  
Irene M Ghobrial ◽  
Nikhil C Munshi ◽  
Brianna N Harris ◽  
Zheng Yuan ◽  
Nichole M Porter ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Dose Level ◽  
Phase Ii ◽  
Research Funding ◽  
Progressive Disease ◽  
Loading Dose ◽  
Advisory Committees ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3

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.

Results of a Phase I Study of Vorinostat In Combination with Pegylated Liposomal Doxorubicin and Bortezomib In Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1955-1955 ◽  
Author(s):  
Peter M Voorhees ◽  
Cristina Gasparetto ◽  
Keren Osman ◽  
Kristy Richards ◽  
Madlyn Ferraro ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Peripheral Neuropathy ◽  
Dose Level ◽  
Research Funding ◽  
Liposomal Doxorubicin ◽  
Systolic Dysfunction ◽  
Pegylated Liposomal Doxorubicin ◽  
Refractory Disease ◽  
Level 3 ◽  
Grade 3

Abstract Abstract 1955 Introduction: The histone deacetylase inhibitor vorinostat has additive to synergistic activity in combination with anthracyclines and proteasome inhibitors in preclinical models of multiple myeloma (MM). We therefore sought to evaluate the safety of vorinostat in combination with pegylated liposomal doxorubicin (PLD) and bortezomib in patients with relapsed and/or refractory MM. Patients and Methods: Treatment consisted of PLD 30mg/m2 on D4, bortezomib 1.3mg/m2 on D1,4,8,11 and escalating doses of vorinostat from either D4-11 or D1-14 of a 3-week cycle. Dose escalation followed a standard “3 + 3” design. Patients could remain on therapy until disease progression or unacceptable toxicity. Key eligibility criteria: relapsed and/or refractory MM, ANC≥1.0×109/L. plts≥100×109/L, CrCl≥30mL/min, adequate hepatic and cardiac function. The primary objective of the study was to determine the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the regimen. Results: 20 patients have enrolled at the following dose levels: The median age was 60 (range 44–73), median time from diagnosis 42.5 months (9 to 117), and median number of prior lines of therapy 2 (1 to 7). 90% of patients received prior immunomodulatory drugs, 65% bortezomib, 65% autologous stem cell transplantation, and 50% anthracyclines. 55% of patients were relapsed; 45% relapsed and refractory. 9 of 13 patients had disease resistant to prior bortezomib-based therapy. Grade 3 and 4 neutropenia was seen in 35% and 5% of patients, respectively, while grade 3/4 lymphopenia and thrombocytopenia were seen in 30%/5% and 10%/20%, respectively. Two grade 3 infections were seen, 1 of which was attributable to study treatment, but no ≥grade 4 infections were encountered. Common non-hematologic toxicities of all grades regardless of attribution included fatigue (70%), anorexia (55%), nausea (80%), vomiting (60%), diarrhea (85%), constipation (70%) and peripheral neuropathy (75%), most of which was grade 1 or 2 in severity. Grade 3 fatigue, peripheral neuropathy and hand foot syndrome were seen in 10% of patients each, while grade 3 diarrhea was seen in 20%. 1 DLT of transient atrial flutter with grade 4 systolic dysfunction was seen at dose level 3. Two of six patients suffered DLTs at dose level 4 consisting of grade 4 thrombocytopenia without bleeding sequelae, thus establishing dose level 3 as the MTD. Serious adverse events included the above mentioned systolic dysfunction and a limited episode of diastolic dysfunction in one patient. No deaths have occurred on study. Using International Myeloma Working Group criteria, 38% of patients have had ≥VGPR and 61% ≥PR. Only 2 of 18 evaluable patients have had progressive disease on treatment. 7 of 10 patients with relapsed disease had ≥PRs, 6 of which were VGPRs, whereas 4 of 8 patients with relapsed and refractory disease responded. 4 of 5 bortezomib-naïve patients responded to treatment and 4 of 4 patients with bortezomib-pretreated but sensitive disease had PRs or better. 3 of 9 patients with bortezomib-refractory disease had ≥PRs but MRs were seen in an additional 3. Conclusions: The MTD of vorinostat in combination with PLD and bortezomib was 400mg on D4-11. Constitutional, gastrointestinal, and neurologic toxicities were common, but predominantly grade 1 and 2 in severity, and largely manageable. Responses were seen in patients with bortezomib-resistant and -sensitive disease. Dose level 3 has been expanded to include an additional 12 patients. Our results support further clinical testing of this combination in patients with MM. Disclosures: Voorhees: Millennium Pharmaceuticals: Speakers Bureau; Celgene: Speakers Bureau. Off Label Use: Vorinostat for the treatment of myeloma. Gasparetto:Millennium Pharmaceuticals: Speakers Bureau; Celgene: Speakers Bureau. Richards:Cephalon: Speakers Bureau; Merck/Shering-Plough: Consultancy. Orlowski:Millennium Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Hurd:Celgene: Research Funding.

Phase I/II Trial of Weekly Escalated Dose Bortezomib Combined with Lenalidomide and Dexamethasone in Patients in First Relapse or Primary Refractory Disease after First Line Therapy for Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4735-4735
Author(s):  
Annemiek Broijl ◽  
Marie José Kersten ◽  
Wendim Ghidey Alemayehu ◽  
Mark-David Levin ◽  
Okke de Weerdt ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Phase 1 ◽  
Median Number ◽  
Phase 2 ◽  
Advisory Committees ◽  
First Line Therapy ◽  
Grade 3

Abstract Background Both Bortezomib and Lenalidomide monotherapy, as well as in combination with dexamethasone and chemotherapy, have shown high overall response rates (ORR) in relapsed and refractory multiple myeloma (RRMM). Recently, the combination of Bortezomib (1.0 mg/m2), Lenalidomide (15 mg) and Dexamethasone was reported to show efficacy in RRMM. (Richardson, Blood 2014) Here, we report the long-time follow-up results of a multicenter, dose-escalating phase I-II trial, HOVON86, which evaluated the effect of weekly escalated dose Bortezomib combined with Lenalidomide and Dexamethasone as reinduction treatment followed by Lenalidomide monotherapy for maintenance treatment in patients with RRMM after first line therapy. (Trial EudraCTnr 2007-002533-37) Methods In the dose escalation part of the study, the maximum tolerated dose (MTD) and recommended dose level (RDL) of weekly Bortezomib and Lenalidomide with Dexamethasone were determined according to a ‘3 + 3' dose-escalation scheme. A maximum of 4 dose levels were planned. Bortezomib was administered once weekly by rapid intravenous administration on days 1, 8, and 15, at a starting dose of 1.3 mg/m2 and planned to be escalated to 1.6 mg/m2, Lenalidomide was administered days 1-21 followed by a one-week interval at a starting dose of 10 mg/day and planned to be increased to 15 mg at dose level 3 and 4. Low dose Dexamethasone was added at a fixed dose of 20 mg days 1,2,8,9,15, and 16. Cycles were repeated at 28 days for a maximum of 8 cycles. The MTD was defined as the level with 2 dose-limiting toxicities (DLT) minus 1 level. A phase II part of the study was performed at the MTD level. All patients received Lenalidomide maintenance at a dose of 10 mg/day, days 1-21 in 28 day cycles until relapse or progression. Patients received valaciclovir prophylaxis with Bortezomib and prophylactic salicylic acid throughout treatment. Results 81 patients with a first RRMM were enrolled, 4 patients were non-eligible based on not having measurable disease. The median age of all 77 evaluable patients at enrollment was 66 years (range, 46–84), 64% male, and 26%/5% of patients had ISS II/III disease. In the Phase 1 part, 15 patients received Bortezomib/Lenalidomide/Dexamethasone according to dose level 1: 1.3 mg/m2/10mg/20mg (n=3), dose level 2: 1.6 mg/m2/10mg/20mg (n=6) or dose level 3: 1.6 mg/m2/15mg/20mg (n=6). The DLT was reached at the 3rd dose level, due to two grade 3 non-hematological DLT's. There were no DLT's in dose level 1 or 2. Therefore, the RDL for the phase 2 part was established at Bortezomib 1.6 mg/m2, Lenalidomide 10 mg, Dexamethasone 20 mg. In the Phase 2 part of the study, the ORR after induction in 70 patients at the RDL of Phase I (n=6) and in Phase II (n=64), was 89%, with 64% CR +VGPR, table 1. The median number of cycles to achieve ≥PR was 1, while the median number of cycles to maximum response was 2. The median duration of response was 28 months. The median progression free survival (PFS) and overall survival (OS) were 19 and 42 months, respectively, Figure 1. The median time to progression was 27 months; the median time to next treatment was 19 months. Prognostic factors associated with PFS included complex karyotype, defined as showing 3 or more abnormalities; no prognostic factors were identified in association with OS. Hematologic toxicity NCI-CTC grade 1-4 occurred in 33/70 (47%) of patients, including 30% grade 3-4. Infectious complications concerned grade 2 in 29% and grade 3 in 16% of patients. Thrombo-embolic events (VTE) occurred in 2 patients (3%). 41/70 (59%) patients developed polyneuropathy (PN) grade ≥ 1; of these 41 patients, 18 patients experienced sensory PN, 2 patients had motor PN, and in 21 cases the type of PN was not further specified. 29 (41%) patients had grade 1-2, and the remaining 12 (17%) patients had grade 3-4 PN. 12/29 (41%) patients received a dose reduction upon development of PN grade 1-2, 11/12 (92%) patients upon development of grade 3-4 PN. 19/29 (66%) patients with grade 1-2 PN showed a complete recovery as compared to 6/12 (50%) patients with grade 3-4 PN. Conclusion Weekly Bortezomib 1.6 mg/m2 plus Lenalidomide 10 mg/day, combined with low-dose Dexamethason is a feasible, effective treatment for relapsed, refractory patients with manageable toxicity. Table 1 Phase 1: n(%) Phase 2: n(%) Total: n(%) Total 6 64 70 CR+VGPR No 3(50%) 2(34%) 25(36%) Yes 3(50%) 42(66%) 45(64%) ORR: ≥PR No 1(17%) 7(11%) 8(11%) Yes 5(83%) 57(89%) 62(89%) Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Kersten: Celgene: 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. Vellenga:Janssen: Research Funding. Bos:celgene: Research Funding. Lokhorst:Genmab: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Sonneveld:Onyx: 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; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1856-1856 ◽  
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.

A Phase I Study of Vorinostat, Lenalidomide, and Dexamethasone In Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Excellent Tolerability and Promising Activity In a Heavily Pretreated Population

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1951-1951 ◽  
Author(s):  
Paul Richardson ◽  
Donna Weber ◽  
Constantine S. Mitsiades ◽  
Meletios A. Dimopoulos ◽  
Jean-Luc Harousseau ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase I Study ◽  
Response Rate ◽  
Advisory Board ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 1951 Background: Although novel treatment combinations for multiple myeloma (MM) have improved outcomes, the disease remains incurable and new drug combinations are urgently needed. Vorinostat is an oral histone deacetylase inhibitor approved in the United States for treatment of patients (pts) with advanced cutaneous T-cell lymphoma who failed prior therapies. Vorinostat alters gene expression and protein activity, promoting MM cell death through multiple pathways, and has been shown in preclinical studies to synergistically enhance the anti-MM activity of bortezomib and immunomodulatory drugs, including lenalidomide, with or without dexamethasone. Aims: The primary objective of this Phase I study was to determine the maximum tolerated dose (MTD) of vorinostat plus lenalidomide and dexamethasone in pts with relapsed or relapsed and refractory MM. Secondary objectives included overall safety, tolerability, response rate, duration of response, and time to progression (TTP). Methods: Pts in this Phase I multicenter open-label study were sequentially enrolled into 1 of 5 escalating doses of the combination regimen using a standard 3 + 3 design for ≤8 cycles. Pts who tolerated treatment and experienced clinical benefit were eligible for enrollment in an extension phase. Toxicity was evaluated using the National Cancer Institute Common Terminology Criteria (version 3.0). Response was assessed using the modified European Group for Blood and Marrow Transplantation criteria and International Myeloma Working Group Uniform Criteria. Safety and efficacy data were analyzed using summary statistics, except for TTP, which was estimated by the Kaplan-Meier method. Results: As of July 15, 2010, 31 pts were treated and evaluable for toxicity; 4 pts remain on study. Most pts had received prior thalidomide (n=22; 71%), bortezomib (n=20; 65%), or lenalidomide (n=14; 45%), with a median of 4 prior therapies (range, 1–10). The patient population contained both high-risk and low-risk pts, based on cytogenetic and/or fluorescence in situ hybridization analyses. Most adverse events (AEs) were mild or moderate in severity. The most common grade ≥3 treatment-related AEs, experienced by 19 (61%) pts, were neutropenia (26%), thrombocytopenia (16%), diarrhea (13%), anemia (10%), and fatigue (10%); 8 pts discontinued due to toxicity. One dose-limiting toxicity (grade 3 diarrhea lasting >48 h) was observed at the maximum assessed dose (level 5), but MTD was not reached (Table) and there were no treatment-related deaths. Among 30 pts evaluable for response, the median TTP was 32 weeks (5 mo), and 4 pts remain on study as of the data cutoff date; 26 of 30 pts (87%) have achieved at least stable disease (SD). Best single responses included 2 complete responses, 3 very good partial responses (VGPR), 11 partial responses (PR), and 5 minimal responses (MR), with 5 pts achieving SD and 4 developing progressive disease, resulting in an overall response rate (ORR; PR or better) of 53%. Of 13 evaluable pts who had previously received lenalidomide, a best single response of SD or better was observed in 9 (69%; 2 VGPR, 3 PR, 1 MR, 3 SD), resulting in a 38% ORR. Notably, SD or better (2 PR, 1 MR, 3 SD) was observed in 60% of 10 evaluable pts who were relapsed, refractory, or intolerant to previous lenalidomide-containing regimens. Conclusions: Preliminary data from this Phase I study suggest that vorinostat plus lenalidomide and dexamethasone is a convenient and generally well-tolerated regimen with promising activity for relapsed or relapsed and refractory MM. The MTD for this combination was not reached. Importantly, responses were observed in pts who had received prior lenalidomide, bortezomib, and thalidomide. Further evaluation of this regimen is planned in future trials. Disclosures: Richardson: Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Vorinostat, Lenalidomide, and Dexamethasone for treatment in Multiple Myeloma. Weber:Novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; Celgene- none for at least 2 years: Honoraria; Millenium-none for 2 years: Honoraria; Celgene, Millenium, Merck: Research Funding. Mitsiades:Millennium: Consultancy, Honoraria; Novartis Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Merck & Co.: Consultancy, Honoraria; Kosan Pharmaceuticals: Consultancy, Honoraria; Pharmion: Consultancy, Honoraria; Centrocor: Consultancy, Honoraria; PharmaMar: Patents & Royalties; OSI Pharmaceuticals: Research Funding; Amgen Pharmaceuticals: Research Funding; AVEO Pharma: Research Funding; EMD Serono: Research Funding; Sunesis: Research Funding; Gloucester Pharmaceuticals: Research Funding; Genzyme: Research Funding. Dimopoulos:MSD: 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. Harousseau:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Houp:Merck Research Laboratories: Employment. Graef:Merck Research Laboratories: Employment. Gause:Merck Research Laboratories: Employment. Byrne:Celgene Corporation: Employment, Equity Ownership. Anderson:Millennium Pharmaceuticals: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; BMS: Consultancy; Acetylon: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene and Millennium: Advisory Board, Speakers Bureau; Merck: Advisory Board.

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3055-3055
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Saima Dean ◽  
Sharon Fung ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Level ◽  
Research Funding ◽  
Response Rate ◽  
Objective Response ◽  
Median Number ◽  
Prior Therapy ◽  
Best Response ◽  
Level 3 ◽  
Grade 3

Abstract Abstract 3055 Lenalidomide (Revlimid®) and dexamethasone is an effective regimen for relapsed/refractory (rel/ref) multiple myeloma (MM) patients (pts) with an overall response rate of 60% and median time to progression of 13.4 months (Dimopoulos ME, et al. Leukemia 2009; 23: 2147-52). We combined lenalidomide with the alkylating agent combination of cyclophosphamide and prednisone—an older regimen with minimal cumulative myelosuppression and good activity as second or third line therapy (Trieu Y, et al, Mayo Clin Proc 2005; 80: 1582). The CPR regimen consisted of cyclophosphamide (CY) on days 1, 8, and 15, lenalidomide on days 1–21 and prednisone 100 mg q 2 days in a 28-day cycle. ASA 81 mg/day was given as DVT prophylaxis. Three dose levels were evaluated using a 3 × 3 dose escalation design. Thirty-two pts were entered between 11/2007-06/2009; median age was 64 (42-80) yrs, 60% were male, and immunoglobulin isotype was IgG in 19 (62%), IgA in 8 (25%) and light chain in 4 (13%) pts. Median β2-microglobulin level was 257 (92-767) nm/L, albumin 39 (34-48) g/L, creatinine 83 (50-126) μmol/L, platelet count 355 (75-479) × 109/L and ANC 2.5 (1.1-6.1) × 109/L. The median number of prior regimens was 2 (1-5). Prior therapy included: ASCT (single in 91%; double in 19%), thalidomide (28%) and bortezomib (50%). FISH cytogenetics were available in 13 pts; 1 had del 13q but none had t(4;14) or del p53. Table 1 summarizes protocol treatment delivered. Table 1. Dose level N Cyclophosphamide dose (mg/m2) Lenalidomide dose (mg) Prednisone dose (mg) Median # cycles given 1 3 150 15 100 12 (12–34+) 2 3 150 25 100 10 (9–23) 3 26 300 25 100 17 (5–28+) 1–3 (All) 32 150–300 15–25 100 19 (5–34+) Dose limiting toxicity was not observed during cycle 1 at any dose level. Grade 3–4 toxicities during the trial included: thrombocytopenia in 7 (22%) and neutropenia in 9 (29%), managed with dose reduction and/or growth factors; five episodes of febrile neutropenia occurred, all at dose level 3. In cohort 3, other grade 3–4 non-hematologic toxicities included 1 episode each of abdominal pain/bacteremia, hypokalemia, fatigue, sick sinus syndrome, cardiac amyloidosis, perforated diverticulum and 2 episodes of DVT. Two heavily pretreated pts developed 2° MDS, including 1 previously treated for lymphoma, 43 and 190 mos after the diagnosis of MM. The best response using modified EBMT criteria was documented at a median of 7 (1-26) cycles and included the following: dose level 1 (1 CR, 2 PR); dose level 2 (1 VGPR, 2 PR); dose level 3 (4 CR, 14 VGPR, 11 PR, 1 MR and 1 stable disease). At a median F/U of 16 (5-34) months, 13 pts remain on study and 18 have progressed at a median of 10 (2-23) mos; 1 was lost to F/U and 9 have died of progressive MM. The 1-year actuarial OS and PFS rates are 93% (95% CI 76–98%) and 78% (95% CI 60–89%), respectively. We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28 day cycle with an acceptable safety profile; 2) the objective response rate (CR + PR + MR) in all 32 pts to date is 94%; 3) the 1-year OS of 93% and PFS of 78% compare favorably with other 3-drug combinations in rel/ref MM pts; 4) further evaluation of this regimen in newly diagnosed pts would be of interest. Disclosures: Reece: Celgene: Honoraria, Research Funding. Off Label Use: Combination of lenalidomide and cyclophosphamide and prednisone in relapsed and refractory myeloma patients. Chen:Celgene Corporation: Consultancy, Honoraria, Research Funding. Kukreti:Celgene: Honoraria.

Impact of Antithymocyte Globulin-Containing Conditioning Regimens on Patients Undergoing Allogeneic Stem Cell Transplantation for Progressive Myelodysplastic Syndrome: A Report From the SFGM-TC Group

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3035-3035
Author(s):  
Ibrahim Yakoub-Agha ◽  
Gandhi Damaj ◽  
Marie Robin ◽  
Stephane Vigouroux ◽  
Alice Garnier ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Refractory Disease ◽  
Advisory Committees ◽  
Grade 3

Abstract Abstract 3035 Background: due to a risk of relapse of underlying disease in patients transplanted with progressive malignancy, the use of antithymocyte globulins (ATG), incorporated within the conditioning regimen prior to allogeneic stem cell transplantation (allo-SCT), is still controversial. We report here on a study of 245 consecutive patients transplanted between January 1999 and December 2009 in 26 French and Belgian centers for progressive MDS, defined as stable, untreated, relapsed or refractory disease. Patients and Methods: Inclusion criteria included patients aged over 18 who received allo-SCT from either a sibling (n=153) or HLA-A, -B, -C, -DRB1 and -DQB1 allele matched unrelated donor (10/10) (n=86) for MDS or AML/RAEB-t (with 20–30% BM blasts). Data quality was ensured using computerized discrepancy errors and vigorous on-site data verification of every single file. A qualified research technicien has been appointed by the University-Hospital of Lille to assist on-site centers that couldn't meet data quality requirements. HLA matching was double-checked by the French Bone Marrow Donor Registry. Results: The first 239 files analyzed until now are presented, including 154 males and 85 females. According to the WHO classification at diagnosis, 85 patients had RA/RARS/RCMD, 86 RAEB1, 62 REAB2 and 6 RAEB-t/AML. Sixty-six patients had progressed to a more advanced disease before allo-SCT. At diagnosis, 102 patients had an IPSS int-2 or higher. Cytogenetic IPSS was recorded as favorable (n=109), intermediate (n=61), unfavorable (n=63) and missing (n=6). Disease status at transplant was established as follows: relapsed or refractory disease (n=106) and untreated or stable disease without hematological improvement (n=133). Median age at transplantation was 53 years (range, 20–70). Patients received myeloablative conditioning (n=105) and nonmyeloablative (n=134) including busulfan-based regimens (n=127), TBI-based regimens (n=92) or other alkylating-agent-based regimens (n=20). In this series, 95 patients (40%) received ATG as part of conditioning ('ATG' group), whereas 144 did not ('no-ATG' group). The analysis reference date of April 1st 2011, median follow-up in survivors was 50 months (IQR, 33–92) with 59 patients having died of relapse and 77 of TRM. The estimated 3-year OS and EFS was respectively 42.3%, and 32.4%. The probability of relapse, overall and event-free survival at 3 years was not significantly different between the two groups. In contrast, the cumulative incidence of grade 2–4 acute GVHD was 48% in the no-ATG group and 30% ATG group (P <.001) and the cumulative incidence of grade 3–4 acute GVHD was 24% and 11% respectively (P <.001). Although the cumulative incidence of chronic GVHD was similar in the no-ATG and ATG groups (64% vs 46%, p=.15), a trend for a lower TRM was observed in the ATG group (22% vs 31%, p=.06). In multivariate analysis, the absence of use of ATG was the strongest parameter associated with an increased risk of acute grade 2–4 [HR = 2.28, 95% CI: 1.39–3.74, p=.001] and grade 3–4 GVHD [HR = 2.19, 95% CI: 1.04–4.61, p=.035]. In conclusion, the addition of ATG to the conditioning regimen resulted in a decreased incidence of acute GVHD without increasing relapse rates and compromising patient survival undergoing allo-SCT for progressive MDS. Disclosures: Yakoub-Agha: Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding; Fresinus: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria. Michallet:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Fresinus: Honoraria, Membership on an entity's Board of Directors or advisory committees. Deconinck:Celgene: Honoraria. Mohty:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Updated Interim Results of the Safety and Efficacy of Different Lenalidomide Starting Dose Regimens in Patients with Relapsed or Refractory (rel/ref) Chronic Lymphocytic Leukemia (CLL) (CC-5013-CLL-009 Study)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3925-3925 ◽  
Author(s):  
Clemens Wendtner ◽  
Michael Hallek ◽  
Graeme Fraser ◽  
Anne-Sophie Michallet ◽  
Peter Hillmen ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Study Drug ◽  
Median Number ◽  
Advisory Committees ◽  
Starting Dose ◽  
Purine Analog ◽  
Equity Ownership ◽  
Grade 3 ◽  
Dose Levels

Abstract Abstract 3925 Introduction: CLL patients (pts) who relapse following purine-analog or bendamustine-based treatments have a poor prognosis. These pts have limited therapeutic options and novel agents with alternative mechanisms of action are needed. Several phase 1 and 2 trials in rel/ref CLL showed promising activity with escalating dose regimens of lenalidomide (LEN). In other phase II studies improved clinical responses to lenalidomide appeared to correlate with dose levels > 5mg/day. This phase 2 trial investigates the safety of LEN initiated at 3 different starting doses followed by a step-wise dose escalation as tolerated in rel/ref CLL. Methods: In this ongoing trial, eligible pts with rel/ref CLL who have received ≥ 1 prior treatment regimen containing purine-analog or bendamustine are being enrolled. The objectives of this study are to evaluate primarily the safety and secondarily the efficacy of different LEN dose regimens. Pts are randomized 1:1:1 to receive a double-blinded starting dose of 5 mg, 10 mg, or 15 mg oral LEN on days 1–28 of each 28-day cycle. In all 3 treatment arms, the dose is escalated by 5 mg increments every 28 days to reach a maximum dose of 25 mg/d, depending on tolerability. In instances of poor tolerability, dose reductions also occur in 5 mg steps. Pts are stratified by relapsed versus refractory status to their last purine-analog or bendamustine-based treatment regimen and according to age (< 65 vs ≥ 65 years). Tumor lysis syndrome (TLS) prophylaxis comprises of oral hydration and allopurinol 300 mg/day and is initiated ≥ 3 days prior to starting study drug and for a minimum of the first 3 treatment cycles. A total of 105 pts are planned for enrollment to the study. Per protocol, unblinded interim analyses were conducted by the independent Data Monitoring Committee (DMC) after 18 subjects completed 1 cycle and continue at 13-week intervals. Results: To date, 95 pts are enrolled at a median age of 64 years (range 32–81). Enrolled pts are primarily male (67%) and Caucasian (92%). Cytogenetic data are available for 73 pts; 21% have del(17p), 55% have del(13q), 25% have del(11q), and of 72 patients evaluable for trisomy 12, 11 patients (15%) tested positive. IGVH is unmutated in 77% of 77 evaluable pts and 44% of 84 evaluable pts are ZAP70-positive. Based on the Binet and Rai staging systems 9 (10%), 25 (26%) and 24 (25%) of subjects are stage A, B and C, respectively; 7 (7%), 12 (13%) and 16 (17%) subjects are low, intermediate or high-risk disease, respectively. For 2 (2%) subjects the Binet/Rai staging is currently unknown. Overall, 19 pts (20%) received prior bendamustine-containing treatment and 71 pts (75%) received prior fludarabine-based treatment. The median number of prior therapies was 3 (range 1–10). Most common hematological grade ≥ 3 AEs include neutropenia (62%) and thrombocytopenia (34%). At baseline, 19% of pts presented with grade 1–2 neutropenia. The most common non-hematological ≥ grade 3 AEs include pneumonia (13%), tumor flare (13%), and fatigue (11%). TLS was reported in 3 pts (3%): grade 1, 3, and 4. In total, 8 grade 5 events were reported, 3 of which were suspected to be related to LEN: 2 cases of pneumonia and 1 death for unknown cause. At the time of the cut-off, 59 pts (62%) have discontinued treatment. Most common reasons for treatment discontinuation include disease progression (n = 20) and AEs (n = 20). To date, 47 pts (49%) have dose escalated above their starting dose levels of which 12 patients escalated to the highest dose level (25 mg daily). 18 subjects have had no dose level reduction or escalations and 1 patient is still in the first cycle of the study. Average duration of treatment is 6.5 cycles, and median number of cycles is 4. Efficacy evaluations are completed monthly after 3 months of study drug treatment. At time of the data reporting, 5 pts were on study drug but did not reach the first assessment at cycle. For the 90 pts evaluable for response, the investigator's assessment indicates 2 pts (2%) reached CR, 36 (40%) achieved PR, 33 (37%) patients had SD, and 19 (21%) pts progressed. Conclusion: The independent DMC, as of 14 June, 2012 (N=95), recommended that accrual into all three treatment arms should continue as planned, suggesting all three starting doses were well tolerated. To date, the ORR is 42% and 49% of pts were dose escalated at least once. In this rel/ref CLL population LEN appears active, and completion of accrual will clarify the appropriate dose at which to initiate therapy. Disclosures: Wendtner: Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: use of lenalidomie in relapsed/refractory CLL. Hallek:Celgene Corporation: Consultancy, Honoraria, Research Funding. Hillmen:Celgene Corporation: Honoraria. Gregory:Celgene Corporation: Honoraria, Research Funding. Stilgenbauer:Celgene Corporation: Honoraria, Research Funding, Speakers Bureau. Kipps:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Purse:Celgene Corporation: Employment, Equity Ownership. Zhang:Celgene Corporation: Employment, Equity Ownership. Mei:Celgene Corporation: Employment.

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 ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4393-4393 ◽  
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.

scholarly journals Phase 1 Trial of Cladribine, High-Dose Cytarabine, G-CSF, and Dose-Escalated Mitoxantrone (CLAG-M) Plus Gemtuzumab Ozogamicin in Adults with Newly-Diagnosed Acute Myeloid Leukemia (AML) or Other High-Grade Myeloid Neoplasm

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3892-3892
Author(s):  
Colin D. Godwin ◽  
Megan Othus ◽  
Mary-Elizabeth M. Percival ◽  
Bart L. Scott ◽  
Pamela S. Becker ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Left Ventricular Systolic Dysfunction ◽  
Phase 1 ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Grade 3

Background: We recently found that CLAG-M was safe and produced higher rates of CR/CRi and higher measurable residual disease (MRD)-negative CR (measured by multiparameter flow cytometry [MFC]) than standard "7+3" therapy in fit patients with newly-diagnosed AML or other high-grade myeloid neoplasm with ≥10% blasts (HG-MN). Since addition of the CD33 antibody-drug conjugate gemtuzumab ozogamicin (GO) to chemotherapy reduces relapse risk and improves survival in some AML patients, we conducted a phase 1 study (NCT03531918) to determine the maximum tolerated dose (MTD) of GO with CLAG-M in fit adults with newly-diagnosed AML (APL excluded) or HG-MN. Patients and Methods: Adults ≥18 years were eligible if they were fit (treatment-related mortality [TRM] score ≤13.1, corresponding to < 13.1% risk of TRM within 1 month) and had LVEF ≥45%, creatinine ≤2.0 mg/dL, and bilirubin ≤2.5-times upper limit of normal. Patients with concomitant illness with expected survival <1 year, with uncontrolled infection, or in myeloid blast phase of chronic myeloid leukemia were excluded. Doses were escalated in cohorts of 6 patients over 2 dose levels of GO ("GO1": 3 mg/m2 on day 1; "GO3": 3 mg/m2 on days 1, 4, and 7 [doses capped 4.5 mg]); the highest dose level achieved could then enroll an additional 6 patients (12 total) if ≤2 dose-limiting toxicities (DLTs) were observed. CLAG-M consisted of cladribine 5 mg/m2/day (days 1-5), cytarabine 2 g/m2/day (days 1-5), G-CSF 300 or 480 μg/day (for weight <76 kg vs. ≥76 kg; days 0-5), and mitoxantrone (18 mg/m2/day; days 1-3). A second course of CLAG-M (without GO) was given if MRD-negative CR/CRi was not achieved. DLT was defined as: 1) any grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7 day delay of the subsequent treatment cycle, with the exception of febrile neutropenia/infection; 2) any grade ≥4 non-hematologic toxicity, with the exception of febrile neutropenia/infection or constitutional symptoms, if recovery to grade ≤2 within 14 days. The protocol was approved by the Fred Hutchinson Cancer Research Center Institutional Review Board. Results: We enrolled 18 patients, median age 66 (range: 28-77) years, median TRM score 3.92 (range: 0.14-10.3) with newly-diagnosed AML (n=14) or HG-MN (n=4); 7 were "favorable", 4 "intermediate and 7 "adverse" by 2017 European LeukemiaNet criteria. The first 6 patients were treated at GO1, with 1 DLT (grade 3 left ventricular systolic dysfunction). Two subsequent cohorts of 6 were treated at GO3. Three DLTs occurred at this second dose level (grade 4 aminotransferase level increase, grade 3 posterior reversible encephalopathy syndrome, grade 3 intracranial hemorrhage). As prespecified in the protocol, with ≤4/12 DLTs the MTD was formally not reached and GO3 was declared the recommended phase 2 dose. Among 18 evaluable patients, 13 achieved CR and 2 CRi for a CR/CRi rate of 83% (95% confidence interval: 59-96%). 13/15 CR/CRi patients were negative for MRD by MFC and cytogenetics for an MRDneg CR/CRi rate of 72% (49-88%). The 3 patients without CR/CRi had marrow aplasia without MFC evidence of AML at time of study removal. Two underwent allogeneic hematopoietic cell transplantation in aplasia; the other achieved later neutrophil recovery prior to AML recurrence 2.5 months following induction without interval therapy. 5/18 did not have platelet recovery to 100,000/µL prior to the next therapy/removal from study. Median time to absolute neutrophil count of 1000/µL (achieved in 16/18 patients) and platelet count of 100,000/µL (achieved in 13/18 patients) was 35 (range: 24-48) days and 31 (range: 26-48) days, respectively. Besides infections and neutropenic fever, hypertension and left ventricular systolic dysfunction were the most common adverse events. One patient had severe, self-limited liver toxicity characterized by weight gain and elevated aminotransferases without hyperbilirubinemia and did not meet typical clinical criteria for sinusoidal obstructive syndrome. There were no deaths within 56 days of starting induction in this study cohort. Conclusions: CLAG-M with fractionated-dose GO is feasible in patients with newly-diagnosed AML/HG-MN and appears to have high anti-tumor efficacy. CR/CRi and MRDneg CR rates were similar to what we observed with CLAG-M alone (86% and 71%, respectively). A phase 2 study based on these findings has been initiated, using event-free survival as primary efficacy endpoint. Disclosures Othus: Celgene: Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Membership on an entity's Board of Directors or advisory committees. Percival:Nohla Therapeutics: Research Funding; Pfizer Inc.: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees. Scott:Agios: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Incyte: Consultancy. Becker:The France Foundation: Honoraria; Accordant Health Services/Caremark: Consultancy; AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding. Gardner:Abbvie: Speakers Bureau. Oehler:Pfizer Inc.: Research Funding; Blueprint Medicines: Consultancy; NCCN: Consultancy. Halpern:Pfizer Pharmaceuticals: Research Funding; Bayer Pharmaceuticals: Research Funding. Walter:Agios: Consultancy; Amgen: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding. OffLabel Disclosure: Cladribine is not approved for AML, only Hairy Cell Leukemia, however it is widely used for AML with literature supporting it.

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