ALBERT

Description: Abstract 306 Introduction: Histone deacetylase inhibitors potentiate the efficacy of anthracyclines and proteasome inhibitors in preclinical models of multiple myeloma (MM). We therefore conducted a phase I clinical trial to evaluate the safety of the histone deacetylase inhibitor, vorinostat, in combination with pegylated liposomal doxorubicin (PLD) and bortezomib for patients with relapsed/refractory MM. Patients and Methods: Patients received bortezomib at 1.3mg/m2 on days 1, 4, 8, and 11; PLD at 30mg/m2 on day 4, and escalating doses of vorinostat (200 to 400mg once daily) on days 4 through 11 of a 3-week cycle. Dose escalation followed a standard “3 + 3” design. Patients remained on therapy until disease progression or unacceptable toxicity. Eligibility criteria included an ANC of ≥1.0×109/L, platelets of ≥100×109/L, a CrCl of ≥30 mL/min., and adequate hepatic and cardiac function. The primary objectives of the study were to establish dose limiting toxicities (DLTs) in cycle 1 and the maximum tolerated dose (MTD) for future phase II testing. Results: Nine patients have enrolled thus far at vorinostat dose levels of 200mg (n=3), 300mg (n=4), and 400mg (n=2). Six patients had relapsed disease, while 3 had relapsed disease that was refractory to their last prior therapy. The median age was 56 (range 44–73), median time from diagnosis was 66 months (range 28 to 117), and median prior number of lines of therapy was 2 (1 to 7). Six of 9 patients received prior bortezomib, 3 of whom were refractory, 7 of 9 had received anthracyclines, 9 of 9 were treated with corticosteroids, 8 of 9 were treated with immunomodulatory agents, and 7 of 9 had undergone autologous stem cell transplantation. One patient was removed from the study at the 300mg vorinostat dose level due to a grade 3 infusion reaction with the first dose of PLD and was not evaluable for DLT or response. Otherwise, there have been no DLTs, serious adverse events, or deaths to date. Common non-hematologic toxicities of all grades have included fatigue (44%), constipation (67%), diarrhea (67%), nausea (56%), vomiting (33%), and peripheral neuropathy (56%), the majority of which were grade 1 and 2 in severity. Grade 3 sensory neuropathy was seen in 2 patients. Common hematologic toxicities of all grades have included neutropenia (44%), lymphopenia (44%), and thrombocytopenia (67%). Grade 3/4 neutropenia, lymphopenia and thrombocytopenia were seen in 2, 3, and 2 patients, respectively. Dose reductions for non-hematologic toxicities have been necessary for 3 patients thus far. Using International Myeloma Working Group criteria, 6 out of 7 evaluable patients have responded to treatment, including 1 complete remission (CR), 1 very good partial remission, and 4 partial remissions (PRs). The only non-responder was assigned to the 200mg vorinostat dose level. PRs were seen in 2 of 3 patients with bortezomib-refractory disease. Conclusions: At the dose levels tested thus far, the addition of vorinostat to the PLD/bortezomib backbone is safe and efficacious in relapsed/refractory MM patients, including those with bortezomib-refractory disease. Cumulative constitutional, gastrointestinal, and neurologic toxicities are common but manageable, and will need to be considered when determining the optimal phase II dose moving forward. Enrollment into the 400mg dose cohort continues. Disclosures: Voorhees: Celgene: Speakers Bureau; Millennium Pharmaceuticals, Inc.: Speakers Bureau. Off Label Use: Vorinostat for the treatment of multiple myeloma. Gasparetto:Millennium Pharmaceuticals: Consultancy, Speakers Bureau. Richards:Cephalon, Inc.: Speakers Bureau. Garcia:Millennium Pharmaceuticals: Speakers Bureau; Celgene: Speakers Bureau. MacLean:Novartis: Speakers Bureau. Foster:Genzyme: Consultancy, Research Funding. Shea:Otsuka: Research Funding; Novartis: Consultancy, Research Funding; Millennium Pharmaceuticals: Research Funding; Genzyme: Consultancy, Research Funding; Genetech: Consultancy. Rizvi:Merck: Employment.

Description: 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.

Description: 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.