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

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.

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

Blood ◽

10.1182/blood.v116.21.2816.2816 ◽

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.

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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 ◽

10.1182/blood.v126.23.3987.3987 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3987-3987 ◽

Cited By ~ 5

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.

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

Blood ◽

10.1182/blood.v114.22.3443.3443 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3443-3443 ◽

Cited By ~ 1

Author(s):

Apostolia-Maria Tsimberidou ◽

William Wierda ◽

William Plunkett ◽

Susan O'Brien ◽

Thomas J. Kipps ◽

...

Keyword(s):

Phase I ◽

Dose Level ◽

Phase Ii ◽

Research Funding ◽

Response Rates ◽

Off Label ◽

Level 3 ◽

Level 1 ◽

Grade 3 ◽

Level 2

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

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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.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e17017 ◽

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.

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Phase I-II Study of Sequential Therapy with Decitabine Followed By Clofarabine, Idarubicin, and Cytarabine (DAC-CIA regimen) in Relapsed/Refractory Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood.v124.21.5283.5283 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5283-5283

Author(s):

Nitin Jain ◽

Farhad Ravandi ◽

Guillermo Garcia-Manero ◽

Gautam Borthakur ◽

Tapan Kadia ◽

...

Keyword(s):

Stem Cell ◽

Dose Level ◽

Stem Cell Transplant ◽

Hematological Toxicity ◽

Cell Transplant ◽

Hypomethylating Agents ◽

Level 1 ◽

Grade 3 ◽

Level 2 ◽

Refractory Aml

Abstract Background: Patients (pts) with relapsed/refractory AML have dismal outcomes with currently available chemotherapy regimens. Preclinical and clinical evidence suggests that the use of hypomethylating agents such as decitabine prior to standard chemotherapy may be synergistic (Qin et al. Clin Can Res 2007; Scandura et al. Blood 2011; Clozel et al. Cancer Discov 2013). Methods: Pts aged ≥18 to 65 years with relapsed or refractory AML (up to salvage 2) were eligible. Prior therapy with hypomethylating agents was allowed. The chemotherapy regimen was as follows: TableDoseDays INDUCTIONDecitabine20 mg/m2 IVDays 1-5Clofarabine15 mg/m2 IVDays 6-9 (Dose level 1) Days 6-10 (Dose level 2)Idarubicin10 mg/m2 IVDays 6-8Cytarabine1 gm/m2 IVDays 6-10CONSOLIDATIONDecitabine20 mg/m2 IVDays 1-5Clofarabine15 mg/m2 IVDays 6-8Idarubicin8 mg/m2 IVDays 6-7Cytarabine1 gm/m2 IVDays 6-8 Results: Eighteenpts (female, n=4) have been treated so far. Median age was 43 years (range 20-61). Majority of the pts (10/18, 56%) were in salvage 2. Four had a prior allogeneic stem cell transplant (SCT). Cytogenetics were diploid (n=4), complex (n=11), 11q abnormality (n=2), trisomy 8 (n=1). Five pts had a TP53 mutation and 3 pts had an NRAS mutation. Median number of cycles administered was 1 (range 1-2). Grade 3-4 non-hematological toxicity included grade 3 mucositis (DLT) in 2 pts during the induction cycle. Due to mucositis and prolonged cytopenias (prolonged cytopenias didn’t meet the DLT definition), dose level 2 was not pursued, and all patients were treated at dose level 1. Grade 3 transaminitis was seen in 4 pts. Fifteen pts had one or more infections. Six (33%) pts achieved CR, of whom 5 were able to proceed to SCT (one pt with CR opted not to pursue SCT). Median time to CR was 35 days. An additional 3 pts had a >50% decrease in bone marrow blast count (marrow response) and all three proceeded with SCT. All 4 patients with diploid cytogenetics achieved CR. Only 1/5 (20%) patients with mutated TP53 achieved a CR. Two patients have relapsed (one 3 months after SCT and the other after consolidation cycle 1). Six patients are alive (4 after stem cell transplant, 2 are receiving further salvage regimens after DAC-CIA failure). Median survival of the entire group is 7.2 months (see figure 1). Conclusions: The sequential treatment of decitabine followed by chemotherapy is safe and effective with a CR rate of 33% and with 8/18 patients able to proceed to an allogeneic SCT. The phase II part of the study is enrolling patients at this time. FIGURE 1 FIGURE 1. Disclosures Off Label Use: Decitabine and clofarabine are not approved for AML..

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

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.4559 ◽

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]

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Phase 1 Study of MDR1 Inhibitor Plus Brentuximab Vedotin in Relapsed/Refractory Hodgkin Lymphoma

Blood ◽

10.1182/blood-2018-99-110403 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1636-1636 ◽

Cited By ~ 2

Author(s):

Robert W. Chen ◽

Lu Chen ◽

Alex F. Herrera ◽

Matthew Mei ◽

Katrina McBride ◽

...

Keyword(s):

Abdominal Pain ◽

Dose Level ◽

Research Funding ◽

Overall Response Rate ◽

Brentuximab Vedotin ◽

Overall Response ◽

Duration Of Response ◽

Level 1 ◽

Grade 3 ◽

Level 2

Abstract Background: Brentuximab vedotin (BV), an antibody drug conjugate (ADC), selectively delivers anti-tubulin agent monomethyl auristatin E (MMAE) to CD 30+ cells. In a multi-center phase II trial in patients with relapsed/refractory Hodgkin lymphoma (HL), BV showed an overall response rate (ORR) of 75%, a complete response (CR) rate of 34%, and a median duration of response (DOR) of 6.7 months (Younes A et al, JCO 2012). Although this drug has high response rates in HL, many patients will eventually develop resistance. We have shown that resistance to BV is associated with upregulation of MDR1 (multidrug resistance pump), and BV resistance cells have a decreased intracellular concentration of MMAE as a result of overexpression of drug export pump (Chen et al, MCT 2015). Cyclosporine (CsA), an immunosuppressant, can inhibit drug export pump by competitive binding. It has been combined with non-targeted chemotherapy to overcome drug resistance in the past without significant benefits. However, it has never been combined with targeted therapies such as antibody drug conjugates. We found that addition of CsA to BV restores intracellular MMAE concentration in BV resistant cell lines and restores the IC50 to BV (Chen ASH 2017). In BV resistant mouse xenograft models, addition of CsA also restores BV sensitivity (Chen ASH 2017). We hypothesize that the combination of CsA and BV is safe and efficacious, thus we designed and conducted a phase I trial using the combination of CsA plus brentuximab vedotin in patients with R/R HL. Patients and Methods: This is a prospective, phase I trial with a 3 + 3 design in patients with relapsed/refractory HL. All patients had biopsy proven relapsed/refractory HL. Three dose levels are planned: 1) 1.2 mg/kg BV every 21 days and 5 mg/kg CsA PO BID on D 1-5, 2) 1.8 mg/kg BV every 21 days and 5 mg/kg CsA PO BID on D 1-5. 3) 1.8 mg/kg BV every 21 days and 7.5 mg/kg of CsA PO BID on D 1-5. DLT period is 21 days. Patients who were relapsed/refractory to BV were allowed. The primary endpoint was MTD. Secondary endpoints were safety, ORR, duration of response, and correlative analysis. Imaging studies were performed every two cycles with alternating CT and CT/PET scans. Response criteria were per Lugano 2014. Results: Thirteen patients were accrued, and all were evaluable for toxicity and 12/13 for efficacy. The baseline characteristics are shown in table 1 and include: previous BV (100%), previous PD1 inhibitor (92%), previous HCT (62%), male predominance (54%), Caucasian predominance (85%), median age of 37, stage III/IV (69%), refractory to previous BV (92%), progressed after PD1 blockade (92%). There was 0 DLT at dose level 1 (0/3), 1 DLT of abdominal pain (grade 3) and neutropenia at dose level 2 in the same patient (1/6 patients), and 4 DLT in 2 out of 3 patients treated at dose level 3. The DLTs were grade 3 hyperglycemia (1), grade 3 bone pain (1), grade 3 constipation (1), and grade 4 lymphopenia (1). Thus dose level 2 is the MTD. Grade 3 or higher possibly-related toxicities (excluding DLT) included neturopenia (6) anemia (4), lymphopenia (3), hyponatremia (3), hypophosphatemia (3), acidosis (1), pneumonitis (1), abdominal pain (1), colitis (1), AST elevation (1), weight loss (1), and hypokalemia (1). Grade II possibly related toxicities >20% included hypertension (46%), peripheral sensory neuropathy (31%), hypophosphatemia (31%), hypokalemia (31%), fatigue (31%), ALT increase (23%), elevated bili (23%), and myalgia (23%). Patients treated at the MTD experienced grade 3/4 possibly-related toxicities that were mainly laboratory based which included: neutropenia (4), anemia (2), hypophosphatemia (2), hypophosphatemia (1), hyponatremia (1), AST elevation (1), lymphopenia (1), abdominal pain (1), and colitis (1). The best overall response (CR+PR) rate was 67%, CR rate was 33%, PR 33%, stable disease rate was 25%, 1 patient was inevaluable. The best overall response rate for patients treated at dose level 1 and 2 was 67% with a CR of 44%. Median number of cycles was 4 (1-14). 2 patients went to autoHCT and 2 patients went to alloHCT after protocol. Conclusion: Addition of CsA to BV is safe and feasible at the MTD. The MTD was determined to be 1.8 mg/kg BV every 21 days plus 5 mg/kg of CsA PO BID on D 1-5. The ORR of 67% and CR of 33 % is very encouraging in a primary BV refractory population. The study has opened the expansion phase. Table 1. Table 1. Disclosures Chen: Millennium Pharmaceuticals: Consultancy, Research Funding; Merck & Co., Inc.: Consultancy, Research Funding, Speakers Bureau; Genentech Inc.: Consultancy; Affimed: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Herrera:Seattle Genetics: Research Funding; Merck, Inc.: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Research Funding; Genentech: Consultancy, Research Funding; Gilead Sciences: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; KiTE Pharma: Consultancy, Research Funding; Immune Design: Research Funding. Siddiqi:Juno Therapeutics: Other: Steering committee. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

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

Blood ◽

10.1182/blood.v116.21.2802.2802 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2802-2802 ◽

Cited By ~ 2

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.

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Azacitidine Priming Prior to R-CHOP Is Feasible and Results in Global Demethylation, Restoration of TGF-Beta Pathway, and Improved Chemotherapy Sensitivity in Patients with Newly Diagnosed DLBCL

Blood ◽

10.1182/blood.v120.21.3706.3706 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3706-3706 ◽

Cited By ~ 1

Author(s):

Rebecca L. Elstrom ◽

Leandro Cerchietti ◽

Peter Martin ◽

Richard R. Furman ◽

ShaoNing Yang ◽

...

Keyword(s):

Dose Level ◽

Hematologic Toxicity ◽

Newly Diagnosed ◽

Tgf Beta ◽

Daily Dose ◽

Level 3 ◽

Level 1 ◽

Grade 3 ◽

Level 2 ◽

Experienced Grade

Abstract Abstract 3706 Background: Diffuse large B cell lymphoma (DLBCL) is potentially curable with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), but many patients either do not respond to treatment or relapse after achieving remission. Since outcomes after relapse are poor, the optimal strategy to improve survival would be to improve initial therapy. Aberrant DNA methylation contributes to the phenotype of many tumors, including DLBCL. DNA methyltransferase inhibitor (MTI) drugs such as azacitidine can reactivate epigenetically silenced genes resulting in direct anti-tumor effects and/or chemosensitization. Preclinical studies show that combination therapy with MTIs and chemotherapy is synergistic in killing DLBCL xenografts while non-toxic to the host. This chemosensitization effect is mediated, in part, by TGF-beta signaling restoration due to SMAD1 demethylation and re-expression. We therefore hypothesized that the combination of the MTI azacitidine with R-CHOP would be feasible and improve outcomes in patients with DLBCL. Methods: We performed a phase I study of epigenetic priming with azacitidine in patients with newly diagnosed DLBCL receiving R-CHOP. Patients were eligible if they had not received previous therapy, had preserved organ function, and did not have active viral hepatitis. Patients were treated with subcutaneous azacitidine daily for 5 days at escalating doses, followed by standard R-CHOP administered on day 8. Cycles were repeated every 21 days for 6 cycles. Hematopoietic growth factor was administered according to ASCO guidelines. Azacitidine dose escalation was undertaken according to the continuous reassessment model using the following dose levels: dose level 1: 25 mg/m2 daily; dose level 2: 50 mg/m2 daily; dose level 3: 75 mg/m2daily. Dose limiting toxicity (DLT) was defined as grade 3 or greater non-hematologic toxicity or grade 4 hematologic toxicity lasting more than 7 days. Neutropenic fever was considered DLT only if grade 4. Tumor and blood samples for correlative studies were obtained prior to initiation of treatment and after cycle one of azacitidine, prior to initiation of R-CHOP. Results: The study has completed accrual, with 12 patients enrolled and treated: one at dose level 1, one at dose level 2, and ten at dose level 3. Eleven patients were of high or high intermediate risk by International Prognostic Index (IPI), and one was of low intermediate risk. Eight patients have completed or discontinued therapy, and 4 remain on treatment. One patient on dose level 3 experienced DLT consisting of hepatitis C reactivation after 2 cycles of study therapy; that patient completed an additional 4 cycles of treatment with CHOP alone. All patients experienced grade 3 or 4 neutropenia, none lasting more than 7 days. Four patients experienced grade 3 neutropenic fever. One patient discontinued study therapy after cycle 1 due to complications of a GI bleed presumed secondary to tumor response; he completed therapy with R-CHOP. All 7 patients who have completed post-treatment restaging have achieved complete remission and are eligible for secondary efficacy analysis. At median follow up of 10 months (range 1.5 to 25 months), one patient (who experienced DLT and completed therapy with CHOP alone) has relapsed. Correlative analysis of tumor and blood samples obtained prior to and after the first cycle of azacitidine show global hypomethylation, decreased SMAD1 promoter methylation and increased SMAD1 expression following azacitidine treatment. Paired patient tumor samples showed improved sensitivity to chemotherapy after treatment with azacitidine ex vivo. Conclusions: Epigenetic priming with azacitidine prior to standard R-CHOP is feasible and shows promising clinical outcomes in patients with previously untreated DLBCL. Correlative studies support a role for TGF-beta signaling pathway in mediating chemosensitization in these patients. Disclosures: Off Label Use: Azacitidine is approved for use in MDS. Discussion here is off label. Martin:Millennium Pharmaceuticals, Inc.: Speakers Bureau. Leonard:Celgene: Consultancy, Honoraria.

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

Blood ◽

10.1182/blood.v116.21.3055.3055 ◽

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.

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