Results Of a Phase 1 Study Of Quizartinib (AC220, ASP2689) In Combination With Induction and Consolidation Chemotherapy In Younger Patients With Newly Diagnosed Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 623-623 ◽  
Author(s):  
Jessica K Altman ◽  
James M. Foran ◽  
Keith W. Pratz ◽  
Denise Trone ◽  
Guy Gammon ◽  
...  
Keyword(s):  
Dose Level ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Phase 1 ◽  
Newly Diagnosed ◽  
Consolidation Chemotherapy ◽  
Phase 1 Study ◽  
Level 1 ◽  
Grade 3 ◽  
Dose Levels

Abstract FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) in acute myeloid leukemia (AML) are associated with early relapse after standard chemotherapy and poor survival. Quizartinib (AC220) is an oral FLT3 receptor tyrosine kinase inhibitor that has shown the highest level of single agent activity seen with a FLT3 targeted agent in FLT3+ relapsed AML to date. This Phase 1 dose escalation study is the first study to report data with quizartinib in combination with standard induction and consolidation chemotherapy in patients aged 18-60 years with newly diagnosed AML, regardless of FLT3-ITD status. The dose escalation was conducted using a modified 3+3 design, where 6 pts were enrolled at each dose level. The pts were given cytarabine 200 mg/m2 x 7 days and daunorubicin 60 mg/m2 x 3 days (7+3) for induction and high dose cytarabine 3 g/m2(HiDAC) q12hours on days 1, 3, and 5 for consolidation. Quizartinib was administered daily for either 7 or 14 days, starting at Day 4 of induction and/or consolidation chemotherapy. Patients were allowed to proceed directly to a stem cell transplant after achieving a response or receive further quizartinib as maintenance therapy after consolidation if they were not transplant eligible. Three dose levels were tested; dose level 1 (DL1) at 60 mg for 7 days, dose level 2 (DL2) 60 mg for 14 days, and dose level -1 (DL-1), 40 mg for 14 days. Through May 31, 2013 18 pts were enrolled in the study, and the safety information at all 3 dose levels are presented. The median age of pts was 43 years (range 22 to 60). Of the 18 patients, 16 had the FLT-ITD mutation. At DL1, one of the 6 patients had a DLT (grade 3 hyponatremia). At DL2, two of the 6 patients had a DLT (grade 3 QTc prolongation and grade 4 pericarditis) which exceeded the pre-specified criteria so DL-1 was then explored. At DL-1, one of the 6 patients had a DLT (grade 3 constrictive pericarditis). The most common (20%) treatment-related adverse events (AEs) were nausea (42%), diarrhea (32%), anemia (26%), febrile neutropenia (26%), neutropenia (21%), fatigue (21%), pyrexia (21%) and thrombocytopenia (21%). The most common (10%) Grade 3 or 4 treatment-related AEs were febrile neutropenia (26%), thrombocytopenia (21%) anemia (21%)), neutropenia (21%), leucopenia (16%), and nausea (11%). The data from this Phase 1 study demonstrates for the first time that quizartinib can be safely administered with induction and/or consolidation chemotherapy in newly diagnosed younger patients with AML. The MTD was identified as 40 mg for 14 days or 60 mg for 7 days. The efficacy results from this Phase 1 study will be available at the time of presentation. Based on these findings, multiple Phase 3 studies in newly diagnosed AML patients are planned. Disclosures: Altman: Novartis: Consultancy; Araid: Consultancy; BMS: Consultancy; Teva: Consultancy; Astellas: Consultancy. Foran:Astellas: Research Funding. Trone:Ambit: Employment. Gammon:Ambit: Employment. Cortes:Ambit: Research Funding.

Results of a Phase 1 Study of Quizartinib (AC220) As Maintenance Therapy in Subjects with Acute Myeloid Leukemia in Remission Following Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 428-428 ◽  
Author(s):  
Brenda M. Sandmaier ◽  
Samer K Khaled ◽  
Betul Oran ◽  
Guy Gammon ◽  
Denise Trone ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Dose Level ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Phase 3 ◽  
Equity Ownership ◽  
Grade 3

Abstract FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) in acute myeloid leukemia (AML) are associated with early relapse after standard chemotherapy and poor survival. Hematopoietic cell transplantation (HCT) is a recommended treatment for patients with FLT3-ITD(+) AML. However, a high rate of relapse after a HCT is observed when compared to FLT3-ITD(-) patients with the 2 year relapse rate of 30% vs. 16% in FLT3-ITD(+) and FLT3-ITD(-) patients, respectively (Brunet, J. Clin. Oncol. 2012). Quizartinib (AC220) is an oral FLT3 receptor tyrosine kinase inhibitor that has shown a high level of single agent activity in nearly 500 patients with FLT3(+) relapsed or refractory AML and is currently in a Phase 3 study. This Phase 1 study examined maintenance therapy with quizartinib in AML patients (aged 18 years or older) in remission after receipt of an allogeneic HCT. Dose escalation was conducted using a modified 3+3 design, where 6 subjects were enrolled at each dose level. Two dose levels were tested; dose level 1 (DL1) at 40 mg and dose level 2 (DL2) at 60 mg given daily in continuous 28 day cycles. Dose limiting toxicities (DLTs) were assessed for the first 2 cycles and subjects were allowed to continue up to a maximum of 24 cycles. Thirteen subjects were recruited and enrollment was completed in June 2013. The median age was 43 (range 23 to 61) years. All subjects had received an HLA-matched allogeneic HCT (3 related and 10 unrelated) a median of 56 (range 41 – 70) days before study enrollment. All subjects were positive for the FLT3-ITD mutation by local testing at the time of diagnosis. Seven subjects were enrolled at DL1, including one who relapsed after 22 days on study and was replaced per protocol as deemed not evaluable for DLTs. There was 1 DLT of Grade 3 gastric hemorrhage which resolved and the subject was able to continue on a reduced dose (30 mg) of quizartinib. Six subjects were enrolled at DL2, including one subject who experienced 1 DLT of Grade 3 anemia but was able to continue on a reduced dose (30 mg). Of the 13 total subjects, 10 (77%) received quizartinib for more than a year. Six (45%) subjects are continuing to receive quizartinib currently (15, 16, 18, 18, 23, and 23 cycles) and 2 (15%) subjects have completed 24 cycles. Three subjects (23%) discontinued due to AE: Grade 4 neutropenia (Cycle 4), Grade 2 corneal epithelium defect (Cycle 9), and Grade 3 autoimmune hemolysis (Cycle 15); 1(8%) discontinued for disease relapse (Cycle 1) and 1 (8%) for protocol non-compliance (Cycle 13). The most common (≥20%) treatment-related adverse events (AEs) were diarrhea (38%; 5 subjects), neutropenia (31%; 4 subjects), nausea (23%; 3 subjects) and leukopenia (23%; 3 subjects). This is the first study conducted to determine whether or not quizartinib can be safely administered as post-transplant maintenance therapy in patients with AML. The data from this study support the use of post-transplant maintenance therapy with quizartinib and show early evidence indicating a reduced relapse rate with only 1 relapse reported out of 13 subjects, which compares favorably to historical reference data. No MTD was identified but 60 mg daily was selected as the highest dose for continuous daily administration based on Phase 2 study data in relapsed or refractory subjects (J Cortes, Blood (ASH Annual Meeting Abstracts) 2013 [Abstract]). Quizartinib maintenance has been included in the current Phase 3 QUANTUM-R study comparing quizartinib vs. salvage chemotherapy in relapsed or refractory FLT3-ITD(+) AML. Disclosures Sandmaier: Astellas Pharma, Inc: Research Funding; Ambit Bioscience Corporation: Research Funding. Khaled:Ambit Bioscience Corporation: Research Funding; Astellas Pharma, Inc: Research Funding. Oran:Astellas Pharma, Inc: Research Funding; Ambit Bioscience Corporation: Research Funding. Gammon:Ambit Bioscience Corporation: Employment, Equity Ownership. Trone:Ambit Bioscience Corporation: Employment, Equity Ownership. Frankfurt:Astellas Pharma, Inc: Research Funding; Ambit Bioscience Corporation: Research Funding.

scholarly journals A Phase 1 Study of Carfilzomib-Thalidomide-Dexamethasone in Patients with Relapsed/Refractory AL Amyloidosis - Catalyst Trial Results

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1890-1890 ◽  
Author(s):  
Mamta Garg ◽  
Andrew Hall ◽  
Matthew Jenner ◽  
Bhuvan Kishore ◽  
Helen J Lachmann ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Partial Response ◽  
Dose Level ◽  
Research Funding ◽  
Phase 1 ◽  
Kidney Injury ◽  
Al Amyloidosis ◽  
Level 1 ◽  
Grade 3 ◽  
Dose Levels

Introduction: Systemic AL amyloidosis is a rare multisystem disease caused by an underlying plasma cell dyscrasia with amyloid fibril deposition causing progressive organ failure. Treatment of the underlying plasma cell disorder underpins the management of AL amyloidosis with bortezomib-based regimes as standard first line treatment. Thalidomide has activity in AL amyloidosis used in low doses in combination with cyclophosphamide and dexamethasone. Carfilzomib (Kyprolis), a second generation irreversible inhibitor of the proteasome, is licenced for treatment of relapsed refractory myeloma. This prospective phase 1 multicentre study was designed to define the maximum tolerated dose (MTD) and recommended dose (RD) of one weekly dose of carfilzomib in combination with a fixed dose of thalidomide and dexamethasone (KTD) in patients with relapsed refractory amyloidosis. Methods and Patients Patients were recruited for treatment with carfilzomib in escalating dose cohorts using a 3+3 dose escalation design at three planned dose levels (Table 1) - all participants received carfilzomib 20mg/m2 on cycle 1 day 1. The primary endpoint was to define the MTD, RD and assess the safety and tolerability of KTD. The key secondary endpoint was a preliminary assessment of the activity of KTD. Results A total of 10 patients were recruited (6 male, 4 female) with a median age of 64 years (30% >70 years). The mean time from AL amyloidosis diagnosis for Dose levels 0 and 1 was 7.8 years (SD ±3.87 yrs.) and 3.2 years (SD ± 1.80) respectively. All non-refractory patients had received at least two previous lines of therapy, with a maximum of four previous lines of therapy. The median creatinine was 77.0µmol/L, the median NT-proBNP was 53.3pmol/L and dFLC at the time of treatment was 77.0mg/L. Three evaluable patients were recruited to Dose Level 0 with no dose limiting toxicities (DLTs) observed. A further 3 evaluable patients were recruited to Dose Level 1 - one patient experienced a DLT (acute kidney injury). Hence, 3 further patients were recruited at this dose level. One participant had a serious adverse event (SAE) following day 1 dosing at 20mg/m2 - deemed not evaluable for DLT assessment as received no further treatment. Three further patients were recruited at Dose level 1 with no further DLT's. The data monitoring committee decided that it was not in the patients' best interest to proceed to Dose level 2, as significant evidence of activity at dose level 1 and concern about potential toxicity. As of June 2019, 7 participants have completed 3 cycles and 4 participants (40%) have completed 6 cycles. Responses were determined centrally according to amyloidosis consensus criteria 2005. The overall hematologic response rate at end of 3 cycles was 70%. This included: complete response - 1 (10%); very good partial response - 3 (30%) and partial response 3 (30%). Of the 3 participants at Dose level 1, 1 participant had a VGPR, 1 had PR and 1 had no response (discontinued at the end of cycle 2). One patient had no response by the end of cycle 2 (discontinued due to toxicity) and 2 patients with DLT's were not assessable for response. A total of 3 participants had SAE's: 1. At dose level 1, grade 3 acute kidney injury which was deemed to be DLT, which recovered with supportive care. 2. At dose level 1, pyrexia, hypotension and hypoxia requiring intensive care admission after day 1 dose of 20mg/m2. There was no clear evidence of infection and this was deemed to be a SAE due to carfilzomib (but not DLT). 3. At dose level 1, grade 3 abdominal pain deemed unrelated to study medication. There were 66 other grade 1 or 2 adverse events reported from 9 participants from the first 3 cycles. There were no SUSARs or deaths in the study reported to date. None of the patients had worsening cardiac function. Results here are preliminary with further endpoints and detail to be presented when all participants have completed therapy. Conclusion This study defined, in combination with thalidomide and dexamethasone, the recommended dose of carfilzomib was 45mg/m2 on days 1, 8 and 15. The MTD of carfilzomib was not reached. Three participants experienced a SAE and a number of participants had grade 1-2 AE's. At the end of 3 cycles, 70% of participants achieved a hematologic response with 40% VGPR or better which appears comparable to other studies in relapsed AL amyloidosis. KTD is a potentially effective regime that can be considered for further study in relapsed refractory systemic AL amyloidosis. Disclosures Garg: Novartis: Consultancy, Honoraria. Hall:Celgene, Amgen, Janssen, Karyopharm: Other: Research funding to Institution. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kishore:Celgene, Jazz, Takeda: Other: Travel expenses; Celgene, Takeda, Janssen: Honoraria, Speakers Bureau. Pitchford:Amgen: Other: Research funding to institution. Flanagan:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Oughton:Amgen: Other: Research funding to institution. Brown:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Wechalekar:Amgen: Research Funding; GSK: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria.

Clinical Safety and Activity In a Phase 1 Study of CAL-101, An Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase P110δ, In Patients with Relapsed or Refractory Non-Hodgkin Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1777-1777 ◽  
Author(s):  
Brad Kahl ◽  
John C. Byrd ◽  
Ian W. Flinn ◽  
Nina Wagner-Johnston ◽  
Stephen Spurgeon ◽  
...  
Keyword(s):  
Clinical Research ◽  
Research Funding ◽  
Phase 1 ◽  
Selective Inhibitor ◽  
Phase 1 Study ◽  
Non Hodgkin Lymphoma ◽  
Duration Of Response ◽  
Equity Ownership ◽  
Grade 3 ◽  
Dose Levels

Abstract Abstract 1777 Introduction: The class I phosphatidylinositol 3-kinases (PI3Ks) regulate cellular functions relevant to oncogenesis. Expression of the PI3K p110δ isoform (PI3Kδ) is restricted to cells of hematopoietic origin where it plays a key role in B-cell proliferation and survival. In non-Hodgkin lymphoma (NHL) cells, constitutive PI3Kδ-dependent PI3K pathway activation is frequently observed. CAL-101 is an isoform-selective inhibitor of PI3Kδ that inhibits PI3K signaling and induces apoptosis of NHL cell lines in vitro. Methods and Patients: This Phase 1 study evaluated the safety, pharmacokinetics and activity of orally administered CAL-101 in patients with relapsed or refractory hematologic malignancies. Sequential cohorts of patients were enrolled at progressively higher dose levels with cohort expansion based on toxicity profile and plasma exposure. CAL-101 was administered orally once or 2 times per day (QD or BID) continuously in 28-day cycles for up to 12 cycles (with the potential for more prolonged therapy on an extension protocol thereafter). Tumor response was evaluated based on standard criteria but without a requirement for PET imaging. Results: At data cutoff, the study had enrolled 55 patients with NHL; 28 patients had indolent NHL (follicular lymphoma n=15, small lymphocytic lymphoma n=6, Waldenstrom's macroglobulinemia n=4, marginal zone lymphoma n=3) and 27 had aggressive NHL (mantle cell lymphoma [MCL] n=18, diffuse large B-cell lymphoma [DLBCL] n=9). Patient characteristics included 69% males (38 vs 17 females), median age [range] of 68 [32-82] years, 44% with refractory disease and 56% with relapsed disease. The median [range] number of prior therapies was 5 [1-12]. The proportion of patients with specific prior therapies included: indolent NHL-rituximab 96%, alkylator 86%, anthracycline 50%, purine analog 36%; aggressive NHL-rituximab 100%, alkylator 100%, anthracycline/anthracenedione 96%, plus bortezomib 72% in MCL patients. CAL-101 dose levels were 50 mg BID (n=2), 100 mg BID (n=11), 150 mg BID (n=8), 200 mg BID (n=16), 350 mg BID (n=9) and 300 mg QD (n=9). The median [range] number of treatment cycles was 4 [1-16], with 16 (29%) patients continuing on treatment (11 on study and 5 on the extension protocol after 12 cycles). Symptomatic adverse events were infrequent, usually low-grade, and not clearly CAL-101-related. Grade ≥3 hematological laboratory abnormalities included neutropenia n= 5 (9%), lymphopenia n=3 (5%), and thrombocytopenia n=3 (5%) with uncertain relationship to CAL-101. Grade≥3 ALT/AST elevations occurred in 18 (33%) patients with onset 2–8 weeks after CAL-101 initiation and resolution 2–4 weeks after CAL-101 interruption; after resolution of ALT/AST changes, most patients were rechallenged at the same or a reduced dose of CAL-101 and the majority of these patients were able to resume treatment without recurrence of transaminase elevations. Partial responses were observed at all dose levels, with respective overall n/N (response rates) in evaluable patients of 15/24 (62%) for indolent NHL, 10/16 (62%) for MCL and 0/9 (0%) for DLBCL. Respective response rates by relapsed or refractory status were 9/13 (69%) and 6/11 (55%) for indolent NHL and 8/11 (73%) and 2/5 (40%) for MCL. The median duration of response had not been reached in indolent NHL patients; 5 patients have had response durations of ≥6 months with response durations ranging to >16 months. The median [range] duration of response was 3 months [1 month to 8 months] in MCL. Pharmacodynamic data have supported drug activity; plasma concentrations of chemokines CCL22 and CCL17 were elevated at baseline and showed significant decreases within 1 cycle of CAL-101 treatment (p<0.001 for both comparisons). An evaluation of pharmacokinetics indicated minimal increases in plasma Cmax and AUC at CAL 101 doses >150 mg BID; these data, taken together with the tumor regression results, have proved helpful in supporting Phase 2–3 dose selection. Conclusions: CAL-101, an oral PI3Kδ isoform-selective inhibitor, shows acceptable safety and promising pharmacodynamic and clinical activity in patients with indolent NHL and MCL. The high rate of tumor regressions and protracted durations of tumor control in heavily pretreated patients support advancing CAL-101 into additional studies, both as a single agent and in combination with chemo/immunotherapy. Disclosures: Kahl: calistoga: Consultancy, Research Funding. Off Label Use: CAL-101 for relapsed lymphoma. Byrd:Calistoga Pharmaceutical Inc.: Equity Ownership. Flinn:calistoga: Research Funding. Wagner-Johnston:calistoga: Research Funding. Spurgeon:calistoga: Research Funding. Furman:GlaxoSmithKline: Clinical research funding, Consultancy, Research Funding, Speakers Bureau; Genentech: Clinical Research Funding, Consultancy, Research Funding, Speakers Bureau; Cephalon: Speakers Bureau, Speakers bureau; Calistoga: Consultancy, Honoraria; Celgene: Clinical Research, Consultancy, Research Funding. Brown:Genzyme: Research Funding; Celgene: Consultancy, Research Funding; Calistoga: Consultancy; Genentech: Consultancy. Coutre:calistoga: Research Funding. Lannutti:Calistoga Pharmaceutical Inc.: Employment. Ulrich:Calistoga Pharmaceuticals: Employment, Equity Ownership. Webb:Calistoga Pharmaceuticals: Employment. Peterman:Calistoga Pharmaceuticals: Employment. Holes:Calistoga Pharmaceuticals: Employment.

Phase 1/2 Trial Of Lenalidomide In Combination With Cyclophosphamide and Prednisone (REP) In Patients With Lenalidomide-Refractory Multiple Myeloma (REPEAT-study)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 287-287 ◽  
Author(s):  
Inger S. Nijhof ◽  
Sonja Zweegman ◽  
Mark-David Levin ◽  
Harry R. Koene ◽  
Aart Beeker ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Dose Level ◽  
Research Funding ◽  
Phase 1 ◽  
Oral Cyclophosphamide ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Grade 3 ◽  
Dose Levels

Abstract Background The outcome of multiple myeloma (MM) patients who are no longer responding to thalidomide, lenalidomide (LEN) and bortezomib (BORT) is very poor, with a median event-free survival of 5 months and median overall survival (OS) of 9 months (Kumar SK et al, Leukemia 2012; 26;149-157). We have previously shown in a small retrospective study that the combination of continuous low dose oral cyclophosphamide (endoxan) and prednisone combined with lenalidomide (REP) had remarkable activity in heavily pretreated LEN-refractory multiple myeloma patients (median 6 lines of previous chemotherapy) (vd Donk et al; Br J Haematol 2010;148(2):335-7). To determine the optimal dose of lenalidomide with continuous cyclophosphamide and prednisone, we initiated a prospective study to evaluate the maximum tolerated dose (MTD) of the REP regimen and to assess its efficacy and safety in LEN-refractory MM patients. Here we report safety and efficacy data from the phase 1 dose-escalation part of the REPEAT-study (NCT01352338). Patients and Methods Patients aged ≥ 18 years with LEN-refractory MM, ECOG-performance status 0-3 and adequate kidney, liver and hematologic function were included. Five dose levels were evaluated using a standard 3+3 design, based on dose-limiting toxicities (DLTs) occurring in cycle 1. Patients received LEN in doses ranging from 10-25 mg/day on days 1-21 of 28-day cycle, while oral cyclophosphamide (50 or 100 mg) and prednisone (20 mg) were given continuously. Therapy was continued until progression. The MTD for the phase 2 part is defined as the highest dose level with 0 or 1 DLT's observed in 6 patients. Results Up till now, 35 patients were enrolled (22 in phase 1 and 13 in phase 2) from August 2011 to June 2013. The phase 2 part is still recruiting and data are not evaluable yet. One patient in phase 1 was excluded because of study violation and is not included in the analysis. The median age of the 21 evaluable patients in phase 1 was 69 years (range 41-73); 76% were male. The median duration of the disease from diagnosis was 41 months (range 18-96), median number of prior therapies was 3 (range 2-6), and 12 patients (57%) had previously received autologous SCT. All patients were LEN-refractory, 19 (90%) had prior BORT treatment, and 16 (76%) had BORT-refractory MM. Fifty-five % of the patients were considered high risk by FISH. At the time of analysis, 16 of 21 patients in phase 1 have discontinued treatment because of disease progression (13), alternative treatment (allo-SCT) (1), or adverse events (2). The MTD was defined as LEN 25 mg days 1-21 of a 28-day cycle, combined with oral cyclophosphamide 50 mg and prednisone 20 mg continuously (dose level 4), based on three patients experiencing a DLT: two developed pneumonia (in dose levels 4 and 5; CTC grade 3), and one patient at dose level 5 experienced CTC grade 3 dyspnea. Neutropenia (18%) and thrombocytopenia (18%) were the most common grade 3 hematological adverse events (AEs), which were managed with growth factor support and/or dose modification. There were no grade 4 hematologic AEs. Grade 3 respiratory tract infections (29%) and grade 2 fatigue (19%) were the most common non-hematological AEs. Venous thromboembolism occurred in 1 patient. Figure 1 shows a waterfall plot of the responses of the patients that participated in the phase 1 part of the study. Overall response rate (≥ PR) was 67% with 6 out of 21 (29%) patients achieving at least VGPR. In addition 2 patients achieved MR (≥ MR: 76%). Median PFS and OS were 6.3 and 15.5 months respectively. Similar results were achieved in the subset of patients with LEN- and BORT-refractory disease. Interestingly, laboratory experiments with purified myeloma cells from these patients suggest synergism between LEN and cyclophosphamide. Conclusions The REP regimen induces high response rates and prolonged PFS and OS in LEN-refractory patients with acceptable toxicity. The MTD is defined as LEN 25 mg days 1-21 of a 28-day cycle, combined with oral cyclophosphamide 50 mg and prednisone 20 mg continuously. Phase 2 is enrolling patients and evaluates efficacy and safety of the REP regimen at the MTD. REP should be considered a valuable salvage option for LEN-refractory MM patients. We will present an updated follow-up at ASH. Disclosures: Sonneveld: Onyx: Research Funding; Millenium: Research Funding; Janssen-Cilag: Research Funding; Onyx: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Celgene: Research Funding. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria. van de Donk:Celgene: Research Funding.

The Combination Of Palbociclib Plus Bortezomib Is Safe and Active In Patients With Previously Treated Mantle Cell Lymphoma: Final Results Of a Phase I Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4393-4393 ◽  
Author(s):  
Peter Martin ◽  
Maurizio DiLiberto ◽  
Christopher E Mason ◽  
Scott A Ely ◽  
Jia Ruan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dose Level ◽  
Research Funding ◽  
Hematologic Toxicity ◽  
Advisory Committees ◽  
Level 3 ◽  
Previously Treated ◽  
Level 1 ◽  
Grade 3 ◽  
Dose Levels

Abstract Introduction Mantle cell lymphoma (MCL) is characterized by cell cycle dysregulation due to cyclin D1 and CDK4 overexpression. Palbociclib (PD 0332991) is an orally bioavailable, specific, reversible inhibitor of CDK4/6 that induces prolonged early G1 arrest (pG1) in MCL cells and durable remissions in patients with MCL. Moreover, we have evidence that palbociclib-induced pG1 sensitizes MCL cells to killing by bortezomib and that sensitization is amplified upon withdrawal of palbociclib, when MCL cells synchronously enter S phase (pG1-S). Targeting CDK4 in combination with bortezomib, therefore, is a rational and novel therapeutic combination. We report the final results of a phase I trial of palbociclib plus bortezomib in patients with previously treated MCL. Methods Adults with previously treated MCL and adequate bone marrow and organ function were received palbociclib orally at doses of 75 mg (dose level 1), 100 mg (dose level 2), or 125 mg (dose levels 3 and 4) for 12 days. Bortezomib was administered by IV or SC injection at 1 mg/m2 (dose levels 1-3) or 1.3 mg/m2 (dose level 4) on days 8, 11, 15, and 18 of each 21-day cycle. Subjects underwent core needle biopsies of tumor tissue pre-treatment, on day 8 (in pG1) and on day 21 (in pG1-S phase) of cycle 1. Subjects were restaged following cycles 2, 5, and 8 and then every 4 cycles. Subjects could remain on the study regimen until progression, unacceptable toxicity, or withdrawal. Dose levels were escalated according to the standard 3+3 schema. Dose limiting toxicity (DLT) was defined as treatment-related grade 3-4 toxicity occurring during cycle 1 or a delay in cycle 2 of > 1 week due to treatment-related grade 4 neutropenia or thrombocytopenia. The primary objective was to estimate the maximum tolerated dose of the combination. Secondary objectives included response rate, duration of response, and evaluation of the pharmacokinetic and pharmacodynamic profiles at multiple time points and across all dose levels. Results Nineteen subjects were enrolled: 6 in dose level 1, 3 in dose level 2, 7 in dose level 3, and 3 in dose level 4. The median age was 64 years (range 42-81). The median number of prior therapies was 3 (range 1-7). The number of subjects with low, intermediate, and high-risk MIPI scores was 6, 11, and 2, respectively. Two subjects experienced DLT: thrombocytopenia (level 1), neutropenia (level 3). Grade 3-4 hematologic toxicity included neutropenia (63%), thrombocytopenia (53%), lymphopenia (32%), and anemia (11%). Treatment-related grade 3-4 non-hematologic toxicity included zoster (1). Grade 1-2 toxicities occurring in >2 pt included: fatigue (47%), pain (42%), bleeding/bruising (37%), increased creatinine (26%), constipation (26%), rash (21%), nausea/vomiting (21%), sensory neuropathy (21%), dyspnea (21%), hypoalbuminemia (16%), cough (16%), edema (16%), infection (16%), increased AST (16%), hypocalcemia (16%), increased alk phos (16%). Reasons for ultimately stopping treatment include: progression (9), toxicity (6), and non-compliance (1). All 3 patients at dose level 4 required dose delays/reductions during cycle 2 due to toxicity. There appeared to be an association with dose of palbociclib and response, with one responder at each of dose levels 1 and 2, and 4 patients remaining free from progression for 1 year at dose level 3, including one complete response. Only one responding patient progressed on therapy. All patients with serial biopsies achieved pG1 on day 8, with reduction in CDK4/CDK6-specific Rb phosphorylation and Ki67 by immunohistochemistry. The primary MCL tumor cells express cell cycle genes scheduled for early G1 such as cyclin D1 and CDK4, but not genes programmed for other phases of the cell cycle such MKi67, E3F3, CDK1, CCNA2, as determined by RNA-seq. Conclusion Daily palbociclib 125 mg for 12 days can be safely combined with bortezomib 1 mg/m2 twice weekly, while higher doses were limited by myelosuppression. The combination induced durable responses in some patients. Palbociclib induced pG1, even at the lowest dose. However, the initial cell cycle control by palbociclib did not predict clinical response. Rather, pG1 appears to induce an imbalance in gene expression that is associated with response to the combination of palbociclib plus bortezomib. Strategies to control the cell cycle and dissect the underpinning mechanisms appear promising in MCL and warrant further evaluation. Disclosures: Martin: Teva: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Speakers Bureau; Millennium: Research Funding; Seattle Genetics: Consultancy, Speakers Bureau. Ruan:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Seattle Genetics, Inc.: Membership on an entity’s Board of Directors or advisory committees. Leonard:Millennium: Consultancy.

A Phase 1/2 Study of G-CSF, Cladribine, Cytarabine, and Dose-Escalated Mitoxantrone (G-CLAM) in Adults with Newly Diagnosed Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1068-1068 ◽  
Author(s):  
Anna B. Halpern ◽  
Megan Othus ◽  
Emily M Huebner ◽  
Kaysey F. Orlowski ◽  
Bart L. Scott ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Research Funding ◽  
Phase 1 ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Grade 3 ◽  
Dose Levels

Abstract Introduction:"7+3" with standard doses of cytarabine and an anthracycline has remained the mainstay of induction chemotherapy for newly diagnosed AML. Since some studies have shown improved outcomes with high-dose cytarabine, cladribine, or escalated doses of anthracyclines, we conducted a phase 1/2 study (NCT02044796) of G-CLAM using escalated doses of mitoxantrone for newly diagnosed AML or high-risk MDS (>10% blasts). Methods: Patients≥18 years were eligible if they had treatment-related mortality (TRM) scores of ≤6.9 (corresponding to a predicted risk of early death with standard induction chemotherapy of ≤6.9%) and adequate organ function (LVEF ≥45%, creatinine ≤2.0 mg/dL, bilirubin ≤2.5 times upper limit of normal). Excluded were patients with uncontrolled infection or concomitant illness with expected survival <1 year. In phase 1, cohorts of 6-12 patients were assigned to 1 of 4 total dose levels of mitoxantrone (12, 14, 16, or 18 mg/m2/day, days 1-3, compared to 10 mg/m2/day used in standard dose G-CLAM previously established in relapsed/refractory AML). Other drug doses were G-CSF 300 or 480 μg/day (for weight </≥76 kg; days 0-5), cladribine 5 mg/m2/day (days 1-5), and cytarabine 2 g/m2/day (days 1-5). In phase 2, patients were treated at the maximum tolerated dose (MTD) of mitoxantrone. A second identical course of G-CLAM was given if complete remission (CR) was not achieved with cycle 1. Up to 4 cycles of consolidation with G-CLA (mitoxantrone omitted) were allowed if CR or CR with incomplete platelet or blood count recovery (CRp/i) was achieved with 1-2 cycles of induction therapy. Dose-limiting toxicities (DLTs) were: 1) grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7-day delay of the subsequent treatment cycle; 2) grade ≥4 non-hematologic toxicity if recovery to grade ≤2 within 14 days, both excluding febrile neutropenia, infection or constitutional symptoms. Results: Among 33 patients (median age of 57.3 [range: 26-77], median TRM score 2.31 [0.16-5.90]) treated in phase 1, one DLT occurred at dose levels 3 and 4 (respiratory failure in both cases), establishing G-CLAM with mitoxantrone at 18 mg/m2/day as the MTD. Sixty-two patients, including 6 treated in phase 1, received G-CLAM at MTD. Patient characteristics were as follows: median age 58 (21-81) years, median TRM score 2.85 (0.06-6.73), with AML (n=52) or high-risk MDS (n=10). Cytogenetics were favorable in 6, intermediate in 44, and adverse in 12 (MRC criteria); 11 patients had NPM1 and 6 had FLT3 mutations. Fifty-two patients (83.9%, 95% confidence interval: 72.3-92.0%) achieved a CR (n=48 [77.4%: 65.0-87.1%]), or CRp/i (n=4 [6.5%: 1.8-15.7%]) with 1-2 cycles of therapy. Only 3 patients required 2 cycles to best response. Among the 48 CR patients, 43 (89.6%) were negative for measurable residual disease (MRDneg) by flow cytometry. Four patients had morphologic leukemia free state, 1 patient with myeloid sarcoma had a partial remission, 4 had resistant disease, and 1 died from indeterminate cause. One patient died within 28 days of treatment initiation (septic shock). Median times to an absolute neutrophil count ≥500/μL and a platelet count of ≥50,000/μL were 26 and 23 days. Besides infections and neutropenic fever, maculopapular rash, and hypoxia (fluid overload/infection-related) were the most common grade ≥3 adverse events. In addition to the phase 1/2 MTD cohort, there were 15 patients treated in an expansion cohort and 3 eligible patients treated off protocol with mitoxantrone at 18 mg/m2. For these 80 patients combined treated at MTD, the CR and CR/CRp/i rates were 76.3% and 81.2%. After multivariable adjustment, compared to 300 patients treated with 7+3 on the SWOG S0106 trial, G-CLAM with mitoxantrone 18mg/ m2 was associated with an increased probability of CR (odds ratio [OR]= 3.08, p=.02), CR/CRp/i (OR=2.96, p=.03), a trend towards improved MRDnegCR (OR= 3.70, p=.06), and a trend towards improved overall survival ([OS]; hazard ratio=0.34, p=.07). For the entire study cohort, the 6 and 12-month relapse-free survival were 73% (64-83%) and 62% (42-74%) and the 6 and 12-month OS were 89% (82- 96%) and 77% (67-88%). Conclusions: G-CLAM with mitoxantrone up to 18 mg/m2/day is well tolerated and has potent anti-leukemia activity. This regimen may warrant further randomized comparison with 7+3. We also plan to examine the addition of sorafenib to G-CLAM in newly diagnosed AML patients regardless of FLT3 status. Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Scott:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees. Becker:GlycoMimetics: Research Funding. Erba:Ariad: Consultancy; Gylcomimetics: Other: DSMB; Pfizer: Consultancy; Sunesis: Consultancy; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Novartis: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Agios: Research Funding; Astellas: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celator: Research Funding; Seattle Genetics: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Amgen: Consultancy, Research Funding.

scholarly journals Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia

2017 ◽  
Vol 93 (2) ◽  
pp. 213-221 ◽  
Author(s):  
Jessica K. Altman ◽  
James M. Foran ◽  
Keith W. Pratz ◽  
Denise Trone ◽  
Jorge E. Cortes ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Phase 1 ◽  
Newly Diagnosed ◽  
Consolidation Chemotherapy ◽  
Phase 1 Study ◽  
Acute Myeloid

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

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

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

scholarly journals Phase 1 Study of Alvocidib (DSP-2033) in Combination with Cytarabine/Mitoxantrone (ACM) or Cytarabine/Daunorubicin (A+7+3) in Japanese Patients (Pts) with Acute Myeloid Leukemia (AML)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-35
Author(s):  
Yasuyoshi Morita ◽  
Takayuki Ikezoe ◽  
Kiyoshi Ando ◽  
Masahiro Onozawa ◽  
Takahisa Yamane ◽  
...  
Keyword(s):  
Research Funding ◽  
Phase 1 ◽  
Tumor Lysis Syndrome ◽  
Newly Diagnosed ◽  
Phase 1 Study ◽  
Chugai Pharmaceutical ◽  
Common Grade ◽  
Otsuka Pharmaceutical ◽  
The Mean ◽  
Grade 3

Background: Alvocidib is a potent cyclin-dependent kinase 9 inhibitor, which has previously been shown to downregulate the B-cell lymphoma-2 family member MCL-1 (myeloid cell leukemia-1) which, in turn, sensitizes tumor cells to apoptotic signals. Alvocidib has been studied globally in relapsed/refractory (R/R) AML in combination with cytarabine/mitoxantrone, as well as in newly diagnosed AML in combination with cytarabine/daunorubicin, and has demonstrated acceptable clinical activity. However, safety and tolerability in Japanese AML pts are unknown. Aims: To evaluate the safety and tolerability of alvocidib administered as ACM or A+7+3. Methods: This multicenter, open-label, uncontrolled phase 1 study (NCT03563560) included 2 regimens: ACM (in pts R/R to cytarabine/anthracycline based intensive chemotherapy and without a cumulative total exposure of anthracycline [daunorubicin-equivalent dose] exceeding 360 mg/m2 at entry) and A+7+3 (in newly diagnosed, treatment naive pts). Key eligibility criteria for both regimens were age 20-64 years, Eastern Cooperative Oncology Group performance status ≤ 2, a left ventricular ejection fraction ≥ 50%, and no major organ dysfunction. The ACM regimen (cohorts R1 and R2) comprised a fixed dose hybrid regimen of alvocidib (30 mg/m2/day as a 30-minute intravenous [IV] bolus followed by 60 mg/m2/day over 4 hours as a continuous IV infusion on days 1-3), and escalating doses of cytarabine (300 or 667 mg/m2/day by continuous IV infusion on days 6-8) and mitoxantrone (14 or 40 mg/m2/day IV infusion on day 9 or 10 starting 12 hours after completing cytarabine) in a standard 3+3 design. In the A+7+3 regimen (cohort F1) the dose of each component was fixed according to the recommended dose from the ongoing phase 1 study in the US (NCT03298984). Treatment consisted of the alvocidib hybrid regimen on days 1-3, cytarabine 100 mg/m2/day by continuous IV infusion on days 5-11, and daunorubicin 60 mg/m2/day IV on days 5-7. The primary study objective was to determine the safety and tolerability of alvocidib in combination with each type of chemotherapy, via the assessment of dose-limiting toxicities (DLTs) and treatment-emergent adverse events (TEAEs; graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03). Secondary objectives were to evaluate the pharmacokinetics (including maximum plasma concentration [Cmax] and area under the concentration-time curve up to the last measurable concentration [AUC0-last]) and clinical activities of these regimens. Results: Between April 2018 to October 2019, 10 pts were enrolled, with a median (range) age of 45.0 (25-64) years. Of these, 6 pts (2 with relapsed disease and 4 with refractory disease) received ACM and 4 pts received A+7+3 (Table). Alvocidib was tolerated and DLTs were not observed in either of the two regimens. The most common TEAEs were hematologic events. The most common Grade ≥ 3 non-hematologic TEAEs occurring in ≥ 2 pts in the ACM regimen were diarrhea (50%), hepatic function abnormal (33%), sepsis (33%), cardiac failure (33%) and hypokalemia (33%). The most common Grade ≥ 3 non-hematologic TEAEs noted in ≥ 2 pts in the A+7+3 regimen were diarrhea (100%), tumor lysis syndrome (50%), and vomiting (50%). In the ACM regimen in R/R AML, all 6 pts were evaluable, of whom 5 (83%) achieved an objective response, including 4 complete remissions (CRs) and 1 morphologic leukemia-free state. The mean duration of CR was 13.6 months. In the A+7+3 regimen in newly diagnosed AML, 3 out of 4 pts were evaluable. All 3 evaluable pts achieved CR. One pt did not complete the A+7+3 regimen due to tumor lysis syndrome and was discontinued from the study prior to disease assessment. Overall, the mean Cmax of alvocidib in plasma was 1241 ng/mL on day 1 and 1217 ng/mL on day 3. The mean AUC0-last was 6555 h*ng/mL on day 1 and 7998 h*ng/mL on day 3. WSummary: Alvocidib in combination with cytarabine 667 mg/m2/day and mitoxantrone 40 mg/m2/day IV infusion in Japanese pts with R/R AML or cytarabine/daunorubicin (7+3) induction in Japanese pts with newly diagnosed AML showed an acceptable safety profile similar to previously investigated regimens in other studies. These data suggest that future studies of alvocidib in hematological malignancies are warranted, and planned directions for alvocidib development include phase 1/2 efficacy and safety studies in combination with other agents. Disclosures Ando: Sumitomo Dainippon Pharma Co., Ltd.: Research Funding. Kiguchi:SymBio Pharmaceuticals., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Honoraria, Research Funding; Daiichi Sankyo Pharmaceutical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Honoraria; Mochida Pharmaceutical Co., Ltd.: Honoraria; Taiho Pharmaceutical Co., Ltd.: Research Funding; Teijin Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; Pfizer Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Novartis Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Sumitomo Dainippon Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Janssen Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Celgene Co., Ltd.: Honoraria, Research Funding; Celltrion, Inc.: Research Funding; Bristol-Myers Squibb Co., Ltd.: Honoraria, Research Funding; MSD Co., Ltd.: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Ono Pharmaceutical Co., Ltd.: Honoraria; Sanofi K.K., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Honoraria, Research Funding; Astellas Pharmaceutical Co., Ltd.: Honoraria, Research Funding. Kasai:Sumitomo Dainippon Pharma Co., Ltd.: Current Employment. Sugimoto:Sumitomo Dainippon Pharma Co., Ltd.: Current Employment. Miyazaki:NIPPON SHINYAKU CO.,LTD.: Honoraria; Otsuka Pharmaceutical: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Novartis Pharma KK: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Celgene: Honoraria.

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.

Sign in / Sign up

Export Citation Format

Share Document