High Response Rate of Romidepsin in Combination with ICE (Ifosfamide, Carboplatin and Etoposide) in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma: Updates of Phase I Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3987-3987 ◽  
Author(s):  
Dai Chihara ◽  
Yasuhiro Oki ◽  
Jason R Westin ◽  
Loretta Nastoupil ◽  
Luis E. Fayad ◽  
...  
Keyword(s):  
Dose Level ◽  
Research Funding ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Median Number ◽  
Peripheral T Cell Lymphoma ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Background: Survival for patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) remains very poor. Outcomes for these patients may be improved by stem cell transplant particularly if in complete remission (CR) prior to transplant (Smith 2013). ICE (ifosfamide, carboplatin and etoposide) and romidepsin single agent are options for the treatment of relapsed/refractory PTCL; however, the CR rate of both treatments is less than 30% (Zelenetz 2003, Mikesch 2013, Coiffier 2012). With the goal of increasing CR rates pre-transplant, we conducted a phase I study of romidepsin in combination with ICE in patients with relapsed/refractory PTCL. Methods: The primary objective of this trial is to determine the toxicity profile and to identify the maximum tolerated dose (MTD) of the romidepsin in combination with standard ICE. Romidepsin was administered intravenously on days 1 and 4 of ICE, at 8mg/m2 (dose level 1), 10mg/m2 (level 2),or 12mg/m2 (level 3). All patients received pegfilgrastrim or filgrastrim for growth factor support. Patients could receive next cycle of treatment on day 14 if ANC was > 1 and platelets were ≥ 75,000 with ≥ 20,000 allowed if patients had bone marrow involvement with PTCL at time of enrollment. Dose escalation was conducted using a modified toxicity probability interval method (Ji 2010). Dose limiting toxicity (DLT) was defined as any grade 3 or 4 non-hematologic toxicity attributed to therapy that could not be controlled or prevented by supportive care or grade 4 thrombocytopenia or neutropenia that lasts for more than 14 days. Results: At the time of the data cut off (August 2015), a total of 17 patients were registered (6 PTCL-NOS, 7 AITL, 1 ALK+ALCL, 1 ALK-ALCL, 1 HSTL, 1 NK/TCL); 15 were evaluable for toxicity and 14 were assessable for response (Cheson 2007). Two, 12 and 1 patients were treated at dose level 1, 2 and 3, respectively. Since DLT with thrombocytopenia was seen in patient who received dose level 3, we continued enrollment in dose level 2. Median age of patients was 60 (range 24-70) years and 10 patients (67%) had primary refractory disease. Median number of prior regimens was 1 (range 1-2) and 1 patient had received a prior front-line consolidative ASCT. Overall, 37 cycles were given to the patients with a median number of treatment cycles of 2 (range 1-4). The median days to the next cycle was 21 days (range: 14-33). Common grade 1/2 non-hematologic toxicities included nausea (51%), vomiting (43%), fatigue (41%) and dyspnea (19%). Grade 3/4 thrombocytopenia, grade 3/4 neutropenia and grade 3 anemia occurred in 95%, 84% and 73% of the cycles; however, febrile neutropenia occurred only in 1 cycle. Dose limiting toxicities included renal failure in dose level 2 and persistent grade 4 thrombocytopenia in dose level 3, and these DLTs led to expansion of dose level 2. The overall response rate was 78% (11/14, 95%CI: 49-95%) with CR rate of 64% (9/14, 95%CI: 35-87%). Three patients each underwent allogeneic and autologous transplant, respectively. Among them, three patients (two after allogeneic and one after autologous transplant), experienced relapse. With censoring the patients at the date of transplant for the survival analysis, median progression-free survival is 10.0 months. Summary: In conclusion, romidepsin plus ICE is an effective salvage regimen but with a higher rate of hematologic toxicities. Despite a relatively high CR rate relapses do continue to occur indicating the need of improving consolidation or maintenance approaches. Treatment of a larger number of patients is underway to optimize the dose of romidepsin when combined with ICE. Disclosures Westin: Spectrum: Research Funding. Nastoupil:AbbVie: Research Funding; Genentech: Honoraria; Janssen: Research Funding; Celgene: Honoraria; TG Therapeutics: Research Funding. Fanale:Celgene: Honoraria.

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

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3443-3443 ◽  
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.

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.

scholarly journals Phase I Study of Romidepsin in Combination with ICE (Ifosfamide, Carboplatin and Etoposide) in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1748-1748 ◽  
Author(s):  
Dai Chihara ◽  
Yasuhiro Oki ◽  
Luis Fayad ◽  
Emily Wesson ◽  
Charnelle Ruben ◽  
...  
Keyword(s):  
Dose Level ◽  
Overall Response Rate ◽  
Bone Marrow Involvement ◽  
Median Number ◽  
Cell Transplant ◽  
Salvage Regimen ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Background: Despite recent approval of 4 new drugs for relapsed PTCL, an unmet need remains for new therapies. Survival of relapsed/refractory PTCL patients is improved by stem cell transplant particularly if patients are in CR prior to transplant (Smith 2013). ICE (ifosfamide, carboplatin and etoposide) is commonly used salvage regimen which produces CR rates ranging from 7% to 23% in patients with PTCL (Zelenetz 2003, Mikesch 2013). Romidepsin is a HDAC inhibitor which showed overall response rate of 25% with CR rate of 15% in a large phase II trial for relapsed/refractory PTCL (Coiffier 2012). To further improve outcomes particularly in CR rates pre-transplant, we conducted a phase I study of romidepsin in combination with standard ICE in patients with relapsed/refractory PTCL. Methods: The primary objective of this trial is to determine the toxicity profile and to identify the maximum tolerated dose of the romidepsin in combination with standard ICE. A statistical design of modified toxicity probability interval method was used (Ji 2010). Romidepsin was administered intravenously on days 1 and 4 of ICE, at 8mg/m2 (dose level 1), 10mg/m2 (level 2), or 12mg/m2 (level 3). All patients received G-CSF support. Patients could receive next cycle of treatment on day 14 if ANC was > 1 and platelets were ≥ 75,000 with ≥ 20,000 allowed if patients had bone marrow involvement with PTCL at time of enrollment. Results: As the time of the data cut off (August 2014), a total of 9 patients were registered (4 PTCL-NOS, 4 AITL, 1 NK/TCL) and 7 were assessable for toxicity and response (Cheson 2007). Two patients were consented but did not received treatment. Median age of patients was 60 (range 59-70) years, 5 patients had primary refractory disease and 5 patients had advanced stage disease at the time of enrollment. Median number of prior regimens was 1 (range 1-2) and 1 patient had received a prior front-line consolidative ASCT. At the time of data cut off a total of 7 patients were treated with 2, 4 and 1 patients respectively at dose level 1, 2 and 3, respectively. Median number of treatment cycles were 2 (range 1-4). The common non-hematologic toxicity of grade 3/4 was fatigue (71%), nausea (43%), shortness of breath (29%), and vomiting (14%). With a total of 15 cycles overall given, grade 3/4 thrombocytopenia and neutropenia occurred in 87% and 40% of the cycles and febrile neutropenia occurred once in 1 patient. Dose limiting toxicities occurred in a 70 year-old female treated at dose level 2 with renal failure which was considered to be associated with ifosfamide and etoposide and in 67 year-old male with bone marrow involvement who previously had a front-line consolidative ASCT 6 months earlier and was treated at dose level 3 with persistent grade 3/4 thrombocytopenia. The overall response rate was 71% (5/7, 95%CI: 22-96%) with all in CR. Two patients who received dose level 1 underwent allogeneic transplant and one patient in dose level 2 underwent autologous stem cell transplant but all patients relapsed after transplant. Median duration of response was 7.2 months and six of the 7 patients experienced further disease progression. Summary: In conclusion, romidepsin plus ICE is an effective salvage regimen but with a higher rate of thrombocytopenia and neutropenia as anticipated than with romidepsin or ICE alone. Even though romidepsin plus ICE produces a high CR rate, early relapse despite this even when followed by transplant indicates the crucial need to develop methods to detect minimal residual disease and approaches to best address this. Enrollment continues to this trial. Disclosures Fanale: Seattle Genetics, Inc.: Consultancy, Honoraria, Other, Research Funding.

Phase 1 Trial of Sorafenib and Everolimus In Patients with Lymphoma or Multiple Myeloma.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2802-2802 ◽  
Author(s):  
Shaji Kumar ◽  
Luis F Porrata ◽  
Stephen M. Ansell ◽  
Joseph P Colgan ◽  
Betsy LaPlant ◽  
...  
Keyword(s):  
Disease Progression ◽  
Dose Level ◽  
Research Funding ◽  
Phase 1 ◽  
Hematologic Toxicity ◽  
Phase 2 ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 2802 Background: Redundancy of pro-survival signaling pathways promotes survival and drug resistance in lymphoid and plasma cell malignancies. In particular, the PI3K-Akt and the MEK-ERK pathways have been shown to play an important role in the proliferation and survival of these malignant cells induced by various cytokines in the tumor microenvironment. Sorafenib, a Raf kinase and VEGF receptor inhibitor, and everolimus, an mTOR inhibitor, have synergistic cytotoxicity in myeloma and lymphoma cells due to inhibition of multiple signaling pathways. Methods: We designed a Phase 1/2 clinical trial to identify the maximum tolerated doses of the two drugs used in combination and the efficacy of the combination. Patients (Pts) with relapsed myeloma or lymphoma were eligible for enrollment. Pts were required to have an absolute neutrophil count ≥1500 × 10(6)/L, a platelet count ≥75,000, and a serum creatinine 21.5 mg/dL. The study utilized the classic 3+3 design. Extensive pharmacokinetic studies were performed to better delineate potential drug interactions. Results: Twenty-six pts were accrued from August 2007 to February 2009. Four pts discontinued sorafenib during cycle 1 for various reasons (2 patient refusal, 1 unrelated medical condition and 1 physician discretion) and were excluded from MTD determination. An additional pt did not have measurable disease and was ineligible, leaving 19 pts with lymphoma (including 6 with Hodgkin lymphoma) and 2 with myeloma for phase I analysis. The pts had a median age of 56 years (range, 22, 69) and were heavily pretreated with a median of 4 prior therapies (range, 1–10). Eighteen (86%) had received a prior stem cell transplant. Four dose limiting toxicities were seen across all dose levels (Table). These included grade 3 vomiting (level 1), grade 4 thrombocytopenia (level 2 and 3, one each) and grade 2 hand and foot rash leading to treatment delay (level 3). Overall, 13 pts experienced a grade 3 or 4 hematologic toxicity. Grade 3 or 4 anemia, neutropenia, and thrombocytopenia occurred in 19%, 43%, and 38% of pts, respectively. Four pts have experienced a grade 3 non-hematologic toxicity; no grade 4 non-hematologic toxicities were seen. Grade 3 non-hematologic toxicities included hypokalemia, weight loss, vomiting, hand-foot skin reaction, fatigue, and elevated alkaline phosphatase. Dose level 1 (sorafenib 200 mg and everolimus 5 mg daily) was best tolerated and was selected for phase 2 evaluation. The ORR was 33% (7/21;95% CI: 15–57%, Table) with 3 pts at dose level 0 (2 PR, 1 CR), one at level 2 (1 PR) and three at level 3 (2 PR, 1 CR) responding. The responders included 5 pts with Hodgkin's disease and one each with an NK cell and T-cell lymphoma. Pts have received a median of 6 cycles (range: 1–19) of treatment. 16 pts have discontinued treatment due to disease progression (13 pts), non-resolution of cytopenias (1 pt), physician discretion (1 pt), and death on study due to lymphoma (1 pt). Disease progression has been seen in 16 pts; 9 pts have died. Median follow-up for pts still alive is 18.7 months (range: 11.5–29.4). 6 pts died from disease progression, one each due to sepsis unlikely related to treatment, cholecystitis, and unknown causes. Sorafenib is metabolized by the cytochrome P450 CYP3A enzyme and RAD-001 mainly by the CYP3A4 system in the liver, hence there is a potential for interactions. The detailed PK analyses performed as part of this trial showed a decrease in the RAD001 levels following initiation of sorafenib on day 8 of cycle 1 (Figure). Conclusion: The combination of sorafenib and everolimus is safe at a recommended phase 2 dose of sorafenib 200 mg and everolimus 5 mg daily. There is no significant drug interaction seen. Activity has been observed, especially in the setting of Hodgkins Disease. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Off Label Use: Lenalidomide for treatment of newly diagnosed myeloma. Witzig:Novartis and Celgene: Patents & Royalties, Research Funding, Served on advisory boards with Novartis and Celgene – both uncompensated with compensation to Mayo Clinic.

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.

Preliminary Safety and Efficacy of the Combination of Brentuximab Vedotin and Ipilimumab in Relapsed/Refractory Hodgkin Lymphoma: A Trial of the ECOG-ACRIN Cancer Research Group (E4412)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 585-585 ◽  
Author(s):  
Catherine S. Diefenbach ◽  
Fangxin Hong ◽  
Jonathon B. Cohen ◽  
Michael J. Robertson ◽  
Richard F. Ambinder ◽  
...  
Keyword(s):  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Checkpoint Inhibitor ◽  
Sensory Neuropathy ◽  
Peripheral Sensory Neuropathy ◽  
Level 1 ◽  
Grade 3 ◽  
Peripheral Sensory ◽  
Level 2

Abstract Background: Despite advances in chemotherapy, R/R HL remains a significant clinical problem with over 1,000 primarily young lives lost annually. HL is a unique tumor in which a small number of malignant Hodgkin Reed-Sternberg (HRS) cells propagate an immunosuppressive microenvironment that augments HRS growth and survival. We hypothesized that immune checkpoint inhibitor therapy could activate the tumor immune microenvironment, while the CD30 expressing HRS cells could be targeted by brentuximab vedotin (BV), thereby overcoming tumor cell resistance and deepening clinical responses. E4412 is a phase 1 ECOG-ACRIN sponsored study of the combination of BV and the checkpoint inhibitors ipilimumab (IPI) and nivolumab (NIVO) in patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL). Here we report the data on the patients treated with BV + IPI, the first cohort of the study. Methods: Patients with biopsy proven R/R HL were treated with BV 1.8mg/kg and two escalating doses of IPI: 1 mg/kg or 3mg/kg. After safety was determined an expanded cohort was treated with BV 1.8mg/kg IV and IPI 3mg/kg IV. The schedule consisted of BV administered every 21 days for 16 cycles and IPI every 21 days x 4 doses and thereafter every 3 months for up to a year. Dose limiting toxicity (DLT) was defined for purposes of dose escalation within the first cycle of therapy. Patients are followed for toxicity up to 30 days beyond their last treatment. Results: As of 7/2015 19 of 23 planned patients have been treated with BV + IPI. We report the data on the full dose escalation population (13 patients: Dose level 1 (6), Dose level 2 (7)). The median age was 33 years (range: 20-49). Seven patients were male. Patients were heavily pretreated with a median of 4 prior therapies (2-13). Fourpatients had prior treatment with BV; 8 patients had prior SCT (7 autologous, 1 allogeneic). Safety: Overall the regimen of BV + IPI was extremely well tolerated with no DLTs noted during dose escalation. Toxicities considered at least possibly related to drug during any cycle of treatment are shown according to grade in Table 1. The most common treatment related adverse events were: diarrhea, rash, and peripheral sensory neuropathy. Other AEs of interest included: alopecia, transaminitis, and uveitis. Grade 3 and 4 treatment related adverse events (AEs) included: Dose level 1: one grade 3 infusion reaction, which led to a protocol amendment to include premedication, no further grade 3 infusion reactions were noted; Dose level 2: one each: grade 3 rash, vomiting, and peripheral sensory neuropathy, and one grade 4 thrombocytopenia in patient with pre-existing thrombocytopenia. Response: For the 12 evaluable patients, the overall response (ORR) for the combination of BV + IPI was 67% with a complete response (CR) rate of 42% (5 of 12 patients). An additional 2 patients had stable disease (SD) giving a clinical benefit rate of 83%. Three of 5 of the CRs occurred at dose level 1 (1mg dose of IPI). The median progression free survival (PFS) is 0.74 years with a median follow-up of 0.66 years. Conclusion: In this first reported study of the combination of checkpoint inhibitor and ADC, toxicity was low, primarily grades 1 and 2. In a heavily pretreated patient population, 33% of whom had had prior BV and 67% of whom were s/p ASCT, the ORR of 67% and CR rate of 42% suggests a potential deepening of response compared to monotherapy. More than half of these CRs occurred at 1mg of IPI suggesting that in combination with ADC, low doses of immune stimulation may be highly active. Optimization of this combination strategy is planned with ongoing accrual to cohorts receiving BV + NIVO, and BV + IPI + NIVO. Data will be updated to include the full BV + IPI cohort by the time of the annual meeting. Table 1. Common and Immune Toxicities Toxicity Type Dose Level 1 (n=6) Dose Level 2 (n=7) Grade Grade 1,2 3 4 5 1,2 3 4 5 (n) (n) (n) (n) (n) (n) (n) (n) Fatigue 5 - - - 3 - - - Fever 1 - - - 3 - - - Pain 2 - - - 3 - - - Alopecia 2 - - - 1 - - - Pruritus 1 - - - 2 - - - Rash maculo-papular 4 - - - 2 1 - - Diarrhea 4 - - - 4 - - - Dyspepsia 2 - - - 1 - - - Nausea 6 - - - 4 - - - Vomiting 3 - - - 2 1 - - Papulopustular rash 1 - - - 1 - - - Alanine aminotransferase increased 3 - - - 3 - - - Aspartate aminotransferase increased 3 - - - 2 - - - Platelet count decreased - - - - - - 1 - Anorexia 3 - - - - - - - Headache 2 - - - 2 - - - Peripheral sensory neuropathy 5 - - - 4 1 - - Dry eye 2 - - - - - - - Uveitis 1 - - - - - - - Cough 2 - - - 1 - - - Disclosures Diefenbach: Molecular Templates: Research Funding; Immunogen: Consultancy; Celgene: Consultancy; Idera: Consultancy; Jannsen Oncology: Consultancy; Gilead: Equity Ownership, Research Funding, Speakers Bureau; Incyte: Research Funding; Genentech: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Off Label Use: Presentation will discuss the experimental use of the checkpoint inhibitor Ipilimumab in relapsed/refractory Hodgkin lymphoma.. Cohen:Celgene: Consultancy; Millennium: Consultancy; Pharmacyclics: Consultancy; Seattle Genetics: Consultancy; BMS: Research Funding; Janssen: Research Funding. Robertson:Eli Lilly: Equity Ownership. Fenske:Pharmacyclics: Honoraria; Seattle Genetics: Honoraria; Millennium/Takeda: Research Funding; Celgene: Honoraria. Kahl:Roche/Genentech: Consultancy; Seattle Genetics: Consultancy; Millennium: Consultancy; Cell Therapeutics: Consultancy; Celgene: Consultancy; Infinity: Consultancy; Pharmacyclics: Consultancy; Juno: Consultancy. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding.

A phase IB trial of 5-azacitidine (5AC) and suberoylanilide hydroxamic acid (SAHA) in patients with metastatic or locally recurrent nasopharyngeal carcinoma (NPC) and NK-T cell lymphoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e17017-e17017
Author(s):  
Wen Son Hsieh ◽  
Eng Huat Tan ◽  
Wan-Teck Lim ◽  
Ross A. Soo ◽  
Anthony T. C. Chan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Viral Load ◽  
Dose Level ◽  
Clinical Benefit ◽  
Tumor Tissue ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

e17017 Background: Epigenetic up-regulation of EBV and cellular genes via demethylation and histone deacetylase inhibition can induce EBV lytic replication enhancing immune mediated tumor killing and up-regulation of tumor suppressor genes resulting in tumor apoptosis. Methods: Patients (Pt) with relapsed or refractory NPC and NK-T cell lymphomas were enrolled to determine safety, tolerability, pharmacokinetics (PK), pharmacodynamics and preliminary anti-tumor activity using a dose escalation design. 5AC was administered on days 1 to 10 sub-cutaneously while SAHA was administered on days 1 to 14 orally. PK for SAHA, EBV viral load, characterization of circulating EBV, Immunohistochemistry (IHC) and EBV promoter methylation analysis in tumor tissue were performed. Results: 11 pt have been treated (M:F 8:3, median age 48, R: 35-71) at 3 dose levels – 5AC 50 mg/m2 and SAHA 200 mg b.i.d. (dose level 1), 5AC 37.5 mg/m2 and SAHA 200 mg q. am and 100 mg q. pm (dose level 2), and 5AC 25 mg/m2 and SAHA 100 mg b.i.d (dose level 3). Median number of previous treatment regimens was 3 (R:1-6). Dose limiting toxicities (DLT) were seen in 2/2 pts at dose level 1: grade 4 thrombocytopenia (1 pt), grade 3 nausea, vomiting and fatigue (2 pts), and grade 5 hepatic failure (1 pt). Two of six patients at dose level 2 experienced DLT: grade 3 fatigue (1 pt) and worsening of pre-existing Sweet’s Syndrome (1 pt). Common AEs (G1/2) included fatigue (73%), cough (64%), anorexia (55%), and injection site reaction (45%). One minor response was seen and 5 pt had prolonged stable disease (>16 weeks), including one patient for 88 weeks. Analysis of post-treatment tumor biopsies showed demethylation of EBV lytic cycle gene promoters after treatment. SAHA PK, IHC results for EBV gene expression in tumor tissue, EBV viral load and characterization of circulating EBV will be presented. Conclusions: 5AC/SAHA appears to be tolerable at dose level 3 with suggestion of clinical benefit. Analysis of post-treatment tumor and blood samples suggests that modulation of EBV gene expression may play a role in the mechanism underlying clinical benefit. Continued accrual at dose level 3 is ongoing. Clinical trial information: NCT00336063.

Phase I dose-finding study of sorafenib in combination with capecitabine and cisplatin as a first-line treatment in patients with advanced gastric cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4559-4559
Author(s):  
C. Kim ◽  
J. Lee ◽  
Y. Choi ◽  
B. Kang ◽  
M. Ryu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Dose Level ◽  
Dose Finding ◽  
Finding Study ◽  
Level 3 ◽  
Dose Finding Study ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

4559 Background: We conducted a phase I dose-finding study of sorafenib (S) in combination with capecitabine (X) and cisplatin (P) in patients with previously untreated metastatic or inoperable advanced gastric cancer. Methods: Four dose levels of S, X, and P combination were tested. The doses of S (p.o. daily), X (p.o. on days 1–14), and P (i.v. on day 1) were escalated at the following schedule; level 1: S 400 mg/d, X 1,600 mg/m2/d, P 80 mg/m2; level 2: S 800 mg/d, X 1,600 mg/m2/d, P 80 mg/m2; level 3: S 800 mg/d, X 2,000 mg/m2/d, P 80 mg/m2; level 1A: S 800 mg/d, X 1,600 mg/m2/d, P 60 mg/m2. The cycle was repeated every 3 weeks. Dose limiting toxicities (DLTs) were evaluated only in the first cycles and a standard 3+3 dose escalation design was implemented. Results: A total 21 pts were enrolled in the study. No DLTs were observed at dose level 1 (n=3). One DLT (grade 3 diarrhea) was noted at dose level 2 (n=6), and 2 DLTs (two grade 4 neutropenias longer than 5 days in duration) were observed at dose level 3 (n=6), which made the level 3 dose the maximum tolerated dose (MTD). However, at cycle 2 and thereafter at dose level 2, the relative dose intensity (RDI) of S and X could not be maintained (mostly below 80%) due to the frequent dose reductions and cycle delays. So, we explored a new dose level (1A) between dose level 1 and 2. Since no DLTs were found in 6 patients at level 1A with RDI mostly above 80% throughout the treatment period, level 1A was determined as recommended dose (RD). Most frequent grade 3 and 4 hematologic toxicities were neutropenia (25.0% of cycles), and most frequent grade 2 and 3 non-hematologic toxicities were hand-foot syndrome (9.4%), asthenia (7.0%), and anorexia (5.5%). The objective responses were confirmed in 10 out of 16 patients with measurable lesions (62.5%; 95% CI, 38.8–86.2%). With a median follow-up of 8.1 months, estimated median progression-free survival was 10.0 months (95% CI, 1.6–18.4 months) and median overall survival has not been reached. Conclusions: Diarrhea and neutropenia were DLTs in this S, X, and P combination. The dose schedule of sorafenib 400 mg po bid daily with capecitabine 800 mg/m2 po bid on days 1–14, and cisplatin 60 mg/m2 iv on day 1 in every 3 weeks is recommended for further development in AGC. [Table: see text]

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.

A Phase 1 Trial of Vorinostat and Pegylated Liposomal Doxorubicin In Relapsed or Refractory Lymphoma.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2816-2816
Author(s):  
Frederick Lansigan ◽  
Stuart Seropian ◽  
Dennis L. Cooper ◽  
Von Potter ◽  
Noelle Sowers ◽  
...  
Keyword(s):  
Dose Level ◽  
Phase 1 ◽  
Pegylated Liposomal Doxorubicin ◽  
Cell Transplant ◽  
Heavily Pretreated ◽  
Level 3 ◽  
Refractory Lymphoma ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 2816 Background: Vorinostat is a histone deacetylase inhibitor with activity in lymphoma and leukemia. Vorinostat has been reported to act synergistically with topoisomeraseII inhibitors such as anthracyclines (Ac) by facilitating an open chromatin configuration thus enhancing double-strand DNA breaks and apoptosis. We conducted a phase 1 study of escalating doses of vorinostat with pegylated liposomal doxorubicin (V+PLD) in patients with relapsed or refractory lymphoma. The primary objective was to determine the maximum tolerated dose (MTD). Other endpoints included safety, tolerability, and activity of V+PLD. Methods: Patients age ≥18 years with relapsed or refractory lymphoma were enrolled sequentially into 1 of 3 dosing levels using a standard 3+3 design for up to 8 cycles. The study was conducted in accordance with the Declaration of Helsinki, good clinical practice and regulatory guidelines. Vorinostat 200 (dose level 1), 300 (dose level 2), or 400mg (dose level 3) twice daily on days 1–7 and PLD 30mg/m2 on day 3 of a 21-day cycle were administered to eligible and consenting patients. CTCAE v.3.0 was used to determine toxicities, and the revised criteria for malignant lymphoma were used to determine response. Results: 14 patients have been enrolled; 2 men and 12 women; median age 69 years [range 27–88]; median prior therapies (4) [1-11]; prior Ac (13); median prior Ac dose (300mg/m2) [108-440mg/m2]; prior HDACi (1); Dose level 1 (7); Dose level 2 (4); Dose level 3 (3). Lymphoma subtypes included: Hodgkin's lymphoma (HL)(4), peripheral T-cell lymphoma (3), diffuse large B-cell lymphoma (DLBCL)(5), grey zone lymphoma (1), lymphoplasmacytic lymphoma (1). Median number of study cycles was two [1-8](2). Grade 3–4 hematologic toxicities included: neutropenia (3) and thrombocytopenia (1). Grade 3–4 non-hematologic toxicities included: fatigue (2), nausea (1), anorexia (1), dehydration (1), AST/ALT elevation (1), amylase/lipase elevation (1). No cardiac toxicities were observed. There was one death attributed to disease progression. Partial responses (PR) were documented in two HL patients, stable disease (SD) in one HL and one DLBCL patient. Three patients continued therapy beyond 2 cycles. One HL patient with a PR tolerated 8 cycles despite a prior anthracycline dose of 350mg/m2 and 9 prior systemic treatments including ABVD, ICE, GND, DICEP, BEAM and autologous stem cell transplant, Gem and C-MOPP. Another HL patient with a PR after 2 cycles is currently on cycle 3 at dose level 3 and had 5 prior treatments including autologous transplant. One other HL patient with SD discontinued therapy after 2 cycles to proceed with alternative chemotherapy including allogeneic stem cell transplant. One patient with cutaneous DLBCL obtained a skin response but had overall stable disease and completed 6 cycles before disease progression; prior treatment included R-CHOP, R-ICE, CEPP, and GemOx. In addition, one patient with lymphoplasmacytic lymphoma had a clinical response after 1 cycle but therapy was discontinued because of neutropenia and her disease progressed. Conclusions: The combination of V+PLD is well tolerated even among older and heavily pretreated patients. There were no cardiac toxicities even in patients heavily pretreated with anthracyclines. The MTD has not been reached and enrollment to dose level 3 is ongoing. Disease control was achieved in 4 of 14 patients (2 PR and 2 SD). Of interest, 3 of 4 patients with HL achieved disease control (2 PR and one SD), and treatment with vorinostat in combination with anthracycline-based therapy warrants further investigation in HL. Disclosures: Lansigan: Merck: Speakers Bureau. Off Label Use: Vorinostat in combination with pegylated doxorubicin is considered experimental in lymphoma. Foss:Merck: Speakers Bureau.

Sign in / Sign up

Export Citation Format

Share Document