A Phase I Study of the HDAC Inhibitor LBH589 in Combination with Imatinib for Patients with CML in Cytogenetic Remission with Residual Disease Detectable by Q-PCR.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2194-2194 ◽  
Author(s):  
Ravi Bhatia ◽  
David S. Snyder ◽  
Allen Lin ◽  
Jennifer Arceo ◽  
Linda Seymour ◽  
...  
Keyword(s):  
Stem Cells ◽  
Phase I ◽  
Research Funding ◽  
Residual Disease ◽  
Leukemia Stem Cells ◽  
Gi Symptoms ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2 ◽  
Dose Limiting Toxicity

Abstract Abstract 2194 Poster Board II-171 Imatinib mesylate (IM) is effective in inducing remission and improving survival in CML patients. However IM-treated patients continue to harbor residual leukemia stem cells (Blood 101:4701, 2003). Most patients relapse if treatment is discontinued, and it is generally recommended that treatment with IM be continued indefinitely. The inability of IM to cure CML, the potential for side effects and the financial burden of life-long treatment provide an impetus to develop approaches to eliminate residual leukemia stem cells. We have shown in preclinical studies that treatment with the HDAC inhibitor LBH589 (LBH) combined with IM effectively eliminates CML stem cells resistant to IM alone. The safety and MTD of LBH589 in combination with Imatinib has not been previously evaluated. We have initiated a phase I, open label clinical trial to determine the safety and tolerability of LBH589 given in combination with IM in CML patients, and to determine the MTD and dose-limiting toxicity (DLT). CML patients in chronic phase (CP) treated with IM 400mg/d for >1 year with major or complete cytogenetic response and residual disease on Q-PCR are eligible. LBH589 is administered in combination with IM 400mg PO daily in 28 day cycles, with successive cohorts of patients receiving escalating doses of LBH 3 times a week (level 1: 10mg; level 2: 15mg; level 3: 20mg). Treatment is scheduled for 6 cycles of 28 days each. Five patients have been enrolled thus far (Table). No dose limiting toxicity (DLT), defined as Grade 3 hematological or non-hematological toxicity in the first 28 days, was observed in 3 patients enrolled at dose level 1. DLT (Grade 3 thrombocytopenia) was observed in 1 of the 2 patients enrolled at dose level 2. Other toxicities included thrombocytopenia (Grade 3 [n=2]; Grade 1-2 [n=4]), hypophosphatemia (Grade 3 [n=1]; Grade 2 [n=2]), fatigue (Grade 1 [n=3]), hypocalcemia (Grade 1 [n=2] and Grade 1-2 GI symptoms (diarrhea [n=2]; nausea [n=3]; anorexia [n=2]; vomiting [n=3]; constipation [n=1]). Of note, significant QTc prolongation was not observed on intensive EKG monitoring. IM did not require to be held for any of these toxicities. Two patients have completed 6 cycles of treatment, with one opting to receive an additional 3 cycles, 2 are currently receiving treatment, and one withdrew after 1.5 cycles because of fatigue and GI symptoms. Bone marrow aspirates for assessment of BCR-ABL status were performed at the end of cycles 3 and 6 of treatment. Q-PCR analyses showed reduction in BCR-ABL levels in patient #2 (LBH 10mg) after 3 months, which was not sustained at 6 months. Patient #4 (LBH 15mg), followed for 5 months so far, had undetectable BCR-ABL after 3 months of treatment. These results suggest that LBH589 can be safely administered in combination with IM. Reduction in BCR-ABL levels was seen in two patients but the durability is unclear as yet. We are continuing accrual of patients to define the MTD and safety of this combination. Disclosures: Bhatia: Novartis: Consultancy, Research Funding. Snyder:Novartis: Consultancy, Honoraria, Speakers Bureau. Deininger:Novartis: Consultancy. Radich:Novartis: Consultancy, Honoraria, Research Funding.

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.

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

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3268-3268
Author(s):  
Martha Q. Lacy ◽  
Kah-Whye Peng ◽  
Stephen J. Russell ◽  
Amylou C. Dueck ◽  
Mrinal M. Patnaik ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Tumor Burden ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

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

A Phase I/II Trial Of Cyclophosphamide, Carfilzomib, Thalidomide and Dexamethasone (CYCLONE) In Patients With Newly Diagnosed Multiple Myeloma: Final Results Of MTD Expansion Cohort

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3179-3179 ◽  
Author(s):  
Joseph R. Mikhael ◽  
Craig B. Reeder ◽  
Edward N. Libby ◽  
Luciano J Costa ◽  
Peter Leif Bergsagel ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Initial Phase ◽  
Research Funding ◽  
Response Rate ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Level 1 ◽  
Grade 3 ◽  
Dose Limiting Toxicity

Abstract Background Carfilzomib is a proteasome inhibitor that irreversibly binds its target and has been validated as both relapse and upfront therapies for multiple myeloma. To optimize pre transplant response, we combined carfilzomib with the widely accessible backbone of cyclophosphamide-thalidomide-dexamethasone (CTD). We previously reported results of the Phase I component of the trial (in which no MTD was reached); we now report results for the MTD and fully accrued expansion cohorts at the MTD of the CYCLONE trial NCT01057225. Methods Newly diagnosed myeloma patients intended for stem cell transplant were eligible. All patients were treated on a 28 day cycle with carfilzomib IV Days 1,2,8,9,15,16 (see Table below for dosing per cohort) along with cyclophosphamide 300 mg/m2 PO Days 1,8,15, thalidomide 100 mg PO Days 1-28 and dexamethasone 40 mg PO Days 1,8,15,22. The initial phase I/ II regimen is shown below – as no DLTs were observed, we increased dosing of carfilzomib to 36 and then 45mg/m2 and have now nearly fully accrued to the Phase II dose level +1 (27mg/m2) and expansion MTD (36mg/m2). Treatment was for 4 cycles with planned SCT post induction. The primary endpoint of the trial is the proportion of patients who have ≥very good partial response (VGPR) to treatment. All patients received herpes zoster prophylaxis and ASA daily. Results A total of 54 patients have been accrued to the trial, 6 in the initial Phase 1, 21 in the initial Phase II (CFZ 27mg/m2), and 27 at CFZ 36-45mg/m2. Median age was 63 (range 27-77) and 52% were male. ISS Stage was advanced (II-III) in 57% The overall partial response rate or better following 4 cycles of CYCLONE at dose level 0 or greater is 91%: CR 18%, VGPR 58%, PR 16%, MR 2%, SD 4%. One patient withdrew from the trial after cycle 1. At dose level 2, 3/7 patients experienced dose-limiting toxicity in cycle 1 including: grade 3 alanine aminotransferase increase (possibly related); grade 3 infusion reaction (probably related); and grade 4 heart failure with grade 3 dyspnea, atrial fibrillation, and fatigue (all possibly related). No dose-limiting toxicity was observed in 6 patients at dose level 1 and thus DL1 was deemed the MTD. Across dose levels, adverse events are fully evaluable in 48 patients. AEs of grade 3 or higher at least possibly related to CYCLONE occurred in 26 (54%) – 35% non hematological and 33% hematological. Most commonly reported non hematological toxicities (all grades) included fatigue (63%), constipation (46%), elevated creatinine (27%), hyperglycemia (27%), lethargy (25%) peripheral sensory neuropathy (25% - all grade 1), and somnolence (21%); however, grade 3/4 toxicities occurring in >5% were uncommon: hypertension (8%), thromboembolic event (6%) and hyperglycemia (6%). Three cases of pneumonia required hospitalization. There were no cardiac events seen in greater than 5% of patients. Grade 3/4 hematological toxicities included lymphopenia (23%) and neutropenia (17%). All patients advancing to SCT successfully collected stem cells. One patient died on study from pneumonia. 90% completed at least 4 cycles. With median follow-up of 16 months (range 0-64), 1-year PFS was 90% and 1-year OS was 98%. Conclusion The 4 drug CYCLONE regimen is highly efficacious with an overall response rate after only 4 cycles of 91% (76% ≥VGPR) at the dosing level of carfilzomib IV 20/27-36 mg/m2 in newly diagnosed myeloma. Toxicities are manageable, with only grade 1 neuropathy and minimal cardiac or pulmonary toxicity. CYCLONE is a combination that results in rapid and deep responses with minimal neuropathy prior to stem cell transplant. Comparative studies of this regimen with longer duration of therapy (as induction or consolidation) at the defined MTD should be considered. Disclosures: Mikhael: Celgene: Research Funding; Onyx: Research Funding; Sanofi: Research Funding. Reeder:Millenium: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Costa:Otsuka: Research Funding. Stewart:Celgene: Honoraria; Millenium: Honoraria, Research Funding; Onyx: Research Funding.

scholarly journals Blinatumomab/Lenalidomide in Relapsed/Refractory Non-Hodgkin's Lymphoma: A Phase I California Cancer Consortium Study of Safety, Efficacy and Immune Correlative Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 760-760 ◽  
Author(s):  
Christina Poh ◽  
Paul Frankel ◽  
Christopher Ruel ◽  
Mehrdad Abedi ◽  
Emily Schwab ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Phase I ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Expansion Phase ◽  
Correlative Analysis ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Introduction Both blinatumomab and lenalidomide have proven, but limited, efficacy in relapsed/refractory (R/R) non-Hodgkin's lymphoma (NHL). Failure of blinatumomab to mediate durable responses is due to its inability to recruit competent cytotoxic T cells which leads to eventual T cell exhaustion. Lenalidomide has been shown to improve efficacy of rituximab through T and NK cell activation even in patients who have previously failed rituximab containing regimens. Based on this, we hypothesized that lenalidomide, when combined with blinatumomab, will enhance its efficacy. We report safety, efficacy and correlative analysis of blinatumomab and lenalidomide in R/R NHL. Methods We conducted a phase I, open-label trial involving patients 18 years and older with R/R CD19+ NHL who have received at least two prior chemotherapeutic or biologic regimens and were not eligible for standard curative options at time of enrollment. Previous CD19-targeted therapy was allowed. Study consisted of a dose escalation followed by a dose expansion phase once the maximum tolerated dose (MTD)/ recommended phase II dose (RP2D) was established using a Phase I Queue modified 3+3 design. The escalation phase has been completed and consisted of blinatumomab continuous infusion (level 1 and 2: 9 mcg/day to 112 mcg/day) from days 1-56 and lenalidomide (level 1: 10 mg and level 2: 20 mg daily) days 29-49 of a 56-day induction cycle. Patients who responded underwent consolidation with blinatumomab continuous infusion days 1-7 and lenalidomide days 1-21 of a 28-day cycle for a maximum of 6 cycles followed by lenalidomide maintenance for 2 years or until unacceptable toxicity or disease progression. Dose limiting toxicities (DLT) included any grade 3/4 drug related adverse events (AE) observed during and up to 7 days after blinatumomab/lenalidomide simultaneous administration. Additional patients were accrued to replace patients who had grade 3/4 AE or progressed before receiving lenalidomide for dose-finding purposes. Primary endpoints included toxicity and determination of the MTD/RP2D during the first 8 weeks of blinatumomab/ lenalidomide induction. Secondary endpoints included overall response rate (ORR), complete response (CR) rate, progression free survival (PFS) which was censored at time of transplant and immune response biomarkers. Results As of July 17, 2019, 18 patients initiated therapy; 7 with diffuse large B cell lymphoma, 3 with mantle cell lymphoma, 3 with follicular lymphoma, 2 with nonspecified B cell lymphoma and 1 each with marginal zone lymphoma, Burkitt's lymphoma and small lymphocytic lymphoma. Median age was 58 (range 30-84) years and the median number of prior regimens was 2.5 (range 2-5); 5 patients had previous stem cell transplant (SCT). 6 patients had disease progression prior to starting lenalidomide. 3 patients received blinatumomab/lenalidomide at dose level 1 with no DLT noted. 9 patients received blinatumomab/lenalidomide at dose level 2 with 4 requiring blinatumomab dose reduction prior to starting lenalidomide. Due to favorable safety profiles with the combination using the MTD/RP2D of lenalidomide 20 daily, upfront doublet therapy was initiated as part of the planned expansion phase. Most common grade 3/4 adverse events were lymphopenia (39%), hypophosphatemia (22%) and hyponatremia (11%). 1 patient (5.5%) experienced grade 3 neurotoxicity. No grade 3/4 cytokine release syndrome or treatment related deaths were seen. At time of data cutoff, three patients remain on active treatment. At a median follow-up time of 14.3 months, ORR was 56% for all patients and 83% (50% CR) for those who received blinatumomab/lenalidomide combination therapy. Median PFS was 3.8 months (95% CI, 1.1 to NR) for all patients and 8.3 months (95% CI, 2.2 to NR) for those who received blinatumomab/lenalidomide combination therapy. 3 patients who achieved response underwent allogeneic SCT and remained in remission for 14.2 to 22.3 months thereafter. Correlative studies are pending and will be reported at time of presentation. Conclusions The combination of blinatumomab and lenalidomide, given at the RP2D dose of 20 mg daily, is safe and well tolerated. This regimen demonstrates encouraging efficacy in this heavily pretreated patient population and is a promising alternative treatment option for R/R NHL patients who are not candidates for aggressive cytotoxic chemotherapy or as a bridge to allogeneic SCT. Disclosures Abedi: Abbie: Speakers Bureau; Takeda: Speakers Bureau; BMS: Speakers Bureau; Celgene: Speakers Bureau; Gilead: Speakers Bureau. Costello:Takeda: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Zain:Seattle Genetics: Consultancy; Spectrum: Consultancy. Budde:F. Hoffmann-La Roche Ltd: Consultancy. William:Defined Health: Consultancy; Techspert: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy; Guidepoint Global: Consultancy. Foss:Spectrum: Other: fees for non-CME/CE services ; Acrotech: Consultancy; miRagen: Consultancy; Eisai: Consultancy; Mallinckrodt: Consultancy; Seattle Genetics: Consultancy, Other: fees for non-CME/CE services . Jonas:AbbVie, Accelerated Medical Diagnostics, AROG, Celgene, Daiichi Sankyo, Esanex, Forma, Genentech/Roche, GlycoMimetics, Incyte, LP Therapeutics, Pharmacyclics: Research Funding; AbbVie, Amgen, Celgene, GlycoMimetics, Jazz, Pharmacyclics, Tolero: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Amgen, GlycoMimetics: Other: Travel expenses. Rosenberg:Amgen: Consultancy, Research Funding. Tuscano:Seattle Genetics: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Research Funding; Spectrum: Research Funding; Takada: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding. OffLabel Disclosure: The use of blinatumomab and lenalidomide in patients with aggressive lymphoma

Final Report of a Phase I Study of Clofarabine Plus High Dose Melphalan as a Conditioning Regimen for Allogeneic Transplantation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 528-528
Author(s):  
Mark Kirschbaum ◽  
Anthony Selwyn Stein ◽  
Paul Frankel ◽  
Leslie Popplewell ◽  
Robert w Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Phase I ◽  
Dose Level ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Level 3 ◽  
Level 1 ◽  
Level 2 ◽  
Reduced Intensity

Abstract Abstract 528 Background: Allogeneic Stem Cell transplantation remains the only curative treatment modality for hematologic malignancies such as AML, ALL, and MDS. Reduced intensity regimens were designed which replaced the alkylating agent cyclophosphamide with the purine nucleoside antimetabolite, fludarabine, a potent immunosuppressive with a substantially milder toxicity profile. Clofarabine is a purine nucleoside analogue designed to exploit a double halogen strategy which confers resistance to adenosine deaminase, increases stability and bioavailability and makes the drug more efficient than fludarabine at inhibiting ribonucleotide reductase (RNR) and disrupting mitochondrial function, leading to apoptosis. Clofarabine is potentially a superior antileukemic agent as compared with fludarabine, thus enhancing the activity of the conditioning regimen. Aims: To evaluate a novel clofarabine containing regimen as conditioning for adult fully matched allogeneic stem cell transplant. Methods: phase I dose escalation: clofarabine (dose level 1 = 30 mg/m2, dose level 2 and 3 =40 mg/m2) IV daily days –7 to day –3 infused over 30 minutes IV, plus Melphalan (dose level 1 and 2, 100mg/m2, dose level 3, 140 mg/m2) administered over 30 minutes IV on day –2. Related or unrelated allogeneic stem cells were infused on day 0. GVHD prophylaxis: initially cyclosporine plus mycophenolate, then tacrolimus plus sirolimus was adopted as per City of Hope standard of care. Patients (pts) age ≥ 18 years with AML, ALL, MDS in either CR1, CR2 or in relapse (up to 50% marrow blasts), not deemed eligible for standard transplant regimens by the attending physician, or at high risk for relapse, are eligible. Results: 16 eligible pts, all with AML, have been treated thus far, 7,males, 9 females, with a median age of 63 years (30 – 66). Seven pts were in CR1, 2 pts were in CR2, 4 pts where induction failures, and 3 pts were in first relapse. Grade 3 non-hematologic toxicities included elevation of transaminases, diarrhea, and hyponatremia. No dose limiting toxicities (DLT) were seen in the 3 pts treated at dose level 1. One patient in dose level 2 died prior to engraftment due to hepatic, renal, and infectious toxicities; that dose level has been expanded to 12 patients and no further DLTs were seen. The first patient treated at dose level 3 developed multiorgan failure and died prior to engraftment. Given the excellent results seen in the two previous cohorts we opted not to dose escalate any further patients beyond clofarabine 40 mg/m2 and melphalan 100 mg/m2. Three patients with primary induction failure received an unrelated donor graft and had complete engraftment and obtained remission. The median time to ANC recovery is 14 days and to platelet recovery is 16 days (see table). Mild acute skin graft versus host disease (GvHD) was seen in five patients, mild chronic GvHD in four patients, one patient developed severe chronic GVHD of the liver and died at day 201 from CNS bleed due to tacrolimus-sirolimus related TTP-HUS. Of the 14 patients that successfully completed transplant (no DLT or engraftment difficulty), only one patient has relapsed, with median follow-up of 10.5 months (range 4–24). Conclusion: The combination of clofarabine and melphalan is a well tolerated reduced intensity conditioning regimen with enhanced anti-leukemia activity leading to complete engraftment of related and unrelated fully matched allogeneic stem cells. Complete engraftment with prolonged disease free survival was seen at both dose levels 1 and 2. Disclosures: Off Label Use: clofarabine as a component of the conditioning regimen for allogeneic transplant.

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.

Phase I study of vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients (pts) with non-Hodgkin lymphoma (NHL) in Japan

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18521-18521 ◽  
Author(s):  
K. Tobinai ◽  
T. Watanabe ◽  
Y. Kobayashi ◽  
S. Yamasaki ◽  
Y. Morita-Hoshi ◽  
...  
Keyword(s):  
Phase I ◽  
Cell Lymphoma ◽  
International Workshop ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Non Hodgkin Lymphoma ◽  
T Cell Lymphomas ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

18521 Background: Vorinostat (Zolinza™), a potent histone deacetylase inhibitor, has demonstrated clinical activity in pts with cutaneous T-cell lymphomas (CTCL) and other NHL subtypes. However, the clinical activity and PK profile in Japanese pts with NHL was unknown. Methods: Japanese pts with NHL were sequentially enrolled in two dose levels ranged from 100 (Level 1) - 200 mg (Level 2) BID, PO for 14 consecutive days every 3 wks. Higher doses were not tested as other phase I studies had established that 300 mg BID for 14 consecutive days every 3 wks exceeded the MTD. PK profiles were analyzed in serum and urine samples. Response was also evaluated according to the international workshop criteria. Results: Ten pts were enrolled: 9 were evaluable for toxicity. One was excluded due to noncompletion of the 1st cycle. All were evaluable for PK. Median age was 60 yrs (range 52–74). Four pts had follicular lymphoma (FL), 2 mantle cell lymphoma (MCL), 2 diffuse large B-cell lymphoma and 2 CTCL. Median no. of prior regimens was 3 (1–4). In the 1st cycle, none of 3 pts at Level 1 and 1 of 6 pts at Level 2 developed DLTs (anorexia and hypokalemia of grade 3), indicating Level 2 to be the MTD in this setting. PK was not greatly affected by multiple doses. Intact drug was hardly excreted in urine (<1% of dose). PK profile is similar to that established in US pts. As of Dec 2006, 4 pts were continuing treatment (median 5 mos [1–15]). Two pts with FL showed PR for 8+ and 2+ mos, respectively, and the remaining 1 pt with FL and 1 of 2 pts with MCL showed tumor reduction greater than 30%. Conclusions: Oral vorinostat was well tolerated up to 200 mg BID for 14 consecutive days every 3 wks in Japanese pts with NHL. Preliminary observations of clinical efficacy warrant further investigations for NHL focusing on FL and MCL. No significant financial relationships to disclose.

A dose-finding study for irinotecan, cisplatin, and S-1 (IPS) in patients with advanced gastric cancer (OGSG 1106).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 144-144
Author(s):  
Hiroki Yukami ◽  
Masahiro Goto ◽  
Takayuki Kii ◽  
Tetsuji Terazawa ◽  
Toshifumi Yamaguchi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Antitumor Activity ◽  
Febrile Neutropenia ◽  
Phase I ◽  
Advanced Gastric Cancer ◽  
Phase I Study ◽  
Fixed Dose ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

144 Background: In Japan, S-1 plus cisplatin is regarded as one of the standard first line treatment of advanced gastric cancer (AGC). However, the prognosis of AGC remains dismal. The development of more effective chemotherapeutic regimen is thus warranted. A combination of irinotecan, cisplatin, and S-1 (IPS) can be a promising triplet therapy for advanced gastric cancer. We conducted a phase I study of IPS to determine the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD) and recommended dose (RD), and to assess its safety and antitumor activity in patients with AGC. Methods: This phase I study was designed and conducted in a 3 + 3 manner to determine the recommended dose (RD) of IPS for the subsequent phase II study. Patients received an escalating dose of intravenous irinotecan (level 1: 100/level 2: 125/level 3: 150 mg/m²) on day 1, a fixed dose of intravenous cisplatin (60 mg/m²) on day 1, a fixed dose of S-1 (80 mg/m² b.i.d.) orally on days 1-14, every 4 weeks. Results: Twelve patients were enrolled between June 2013 and February 2017. During the first cycle, one of the six patients in level 1 and two of six patients in level 2 developed the DLT (grade 4 leucocytopenia and grade 3 febrile neutropenia). The MTD of irinotecan was 125 mg/m 2 (level 2) and the RD of irinotecan was considered to be 100 mg/m² (level 1). The most common grade 3 or 4 adverse events included neutropenia 75 % (9/12), anemia 25% (3/12), anorexia 8% (1/12), and febrile neutropenia 17% (2/12). Among six patients with measurable lesions, the response rate was 66.7% (4/6) [95% CI, 33.3-90.7%]. Two patients were performed R0 resection after IPS, with one patient achieved pathological complete response. The median survival time is under analysis. Conclusions: RD of IPS was determined to be 100 mg/m² of irinotecan, 60 mg/m² of cisplatin, and 80 mg/m² of S-1. Our data showed that this regimen provided acceptable antitumor activity and a favorable toxicity profile. Further evaluation of this regimen is warranted. Clinical trial information: UMIN000006864.

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/II Study of Lenalidomide (R) with Low Dose Dexamethasone (d) and Cyclophosphamide (C) for Patients with Primary Systemic (AL) Amyloidosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 428-428 ◽  
Author(s):  
Efstathios Kastritis ◽  
Maria Roussou ◽  
Magdalini Migkou ◽  
Konstantinos Pamboukas ◽  
Maria Gavriatopoulou ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Low Dose ◽  
Alkylating Agents ◽  
Al Amyloidosis ◽  
Hematologic Response ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 428 Lenalidomide (R) has significant activity in patients with multiple myeloma (MM). R has also shown activity in patients with AL amyloidosis, especially in combination with dexamethasone (D). However, AL patients are usually frail and R at the standard dose of 25 mg/day has been associated with significant toxicity. In MM patients, R with low dose D (Rd) has a better toxicity profile than the combination of R with high dose D. Alkylating agents, such as cyclophosphamide (C), are active in patients with AL and combinations of R with alkylating agents have given promising results in patients with MM. Thus, we designed a phase I/II trial of R, with low dose D and low dose C (RdC) in patients with AL. Primary objective of the study was to determine the maximum tolerated dose (MTD) for RdC and to assess hematologic response. Patients receive D 20 mg on days 1-4 (total 80 mg per cycle) , C on days 1-10, R on days 1-21 every 28 days, according to dose level (level 0: R 10 mg, C 50 mg, level 1: R 10 mg, C 100 mg, level 2: R 15 mg, C 100 mg). In the phase I part of the study, patients were observed for 2 cycles for determination of Dose Limiting Toxicity (DLT) according to a standard 3+3 design. Patients with a creatinine ≤2.5 mg/dL and adequate hepatic function were enrolled. All patients receive low-dose aspirin or LMWH if indicated. So far 23 patients have been enrolled in the study (16 in phase I, 7 in phase II). In the phase I study, 3 patients were enrolled in dose level 0, 7 in dose level 1 and 6 in dose level 2. Dose level 2, (R 15 mg, C 100 mg) is being further explored; 7 patients have been enrolled in phase II and accrual is ongoing. So far, 132 cycles of therapy have been administered; 8 patients have receive ≥6 cycles of RdC and 3 have completed 12 cycles of treatment. According to consensus criteria, heart was involved in 65%, kidneys in 61%, liver in 9% and 17% had AL-related peripheral neuropathy; 95% of the patients were Mayo stage II or III. Most patients (70%) were previously untreated. Among 7 pretreated patients, 2 had refractory disease, 2 had prior thalidomide and 5 had prior bortezomib. Hematologic response rates for patients who received at least 2 cycles of treatment, among all cohorts, was 64% and for the patients treated at dose level 2 was 75%. Median time to hematologic response was 2.5 months (range 0.9-4.8 months) for all patients and 1 month (range 0.9-2.9) for those treated at dose level 2. Organ responses have been recorded in 5 patients so far (3 cardiac and 3 renal responses, 1 patient had both cardiac and renal response). After a median follow-up of 7 months, 7 patients have died; 5 due to progressive heart amyloid, one patient had an acute MI followed by acute stent thrombosis and one died due to sepsis. The most common hematologic toxicities were anemia (grade 3/4 in 17%) and neutropenia (grade 3/4 in 17%). Most common non-hematologic toxicities were infection (grade ≥3 in 22%), fatigue (grade ≥3 in 9%), and rash (in 22%, grade 3 in 4%); also one patient suffered a stroke and one had DVT while on treatment with RdC. In parallel, and on a compassionate basis, AL patients with creatinine >2.5 mg/dL or on dialysis, were offered RdC with R dose adjusted according to CrCl. Initially R was given 15 mg every other day for CrCl <30 ml/min, or 15 mg thrice per week on the day after dialysis but due to toxicity R dose was reduced to 10 mg. So far, 13 patients have been treated with attenuated-dose RdC: 3 patients achieved a CR, one achieved a cardiac and one patient a liver response. However, the non-hematologic toxicity of the combination in patients with renal impairment was significant including fatigue (53%), infections (38%), rash (31%), diarrhea (15%), hyponatriemia (15%). Three patients discontinued treatment due to toxicity after the 1st cycle (including one early death due to non-neutropenic infection). In conclusion, RdC is an effective oral regimen for patients with AL amyloidosis, inducing significant rates of hematologic and organ responses. The recommended dose for RdC was R at dose of 15 mg, C at a dose of 100 mg and 20 mg of D and is further evaluated in the phase II of the study. Toxicity is manageable for patients with serum creatinine <2.5 mg/dL but can be significant for AL patients with more severe renal impairment. Lower doses of R, at 10 mg or less every other day or thrice per week should be used in these patients. Accrual in the phase II study is ongoing and updated results will be presented at the meeting. Disclosures: Dimopoulos: Celgene: Honoraria, Research Funding.

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