scholarly journals Relationship Between Response and Dose in Published, Contemporary Phase I Oncology Trials

2020 ◽  
Vol 18 (4) ◽  
pp. 428-433
Author(s):  
Antonious Hazim ◽  
Gordon Mills ◽  
Vinay Prasad ◽  
Alyson Haslam ◽  
Emerson Y. Chen
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Response Rate ◽  
Dose Range ◽  
Drug Dose ◽  
Cancer Type ◽  
Drug Study ◽  
Median Response ◽  
Median Response Rate ◽  
The Relationship

Background: As progress continues in oncology drug development, this study aimed to examine whether the previously established association between drug dose and efficacy in the era of cytotoxic therapies remains true in today’s phase I dose-escalation oncology trials. Methods: A systematic review of early-phase dose-finding trials of single-agent oncology drugs from 2015 to 2018 was conducted to examine the relationship between drug dose and objective responses. Cancer-specific trials were included if they determined maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D). Data related to the study drug, study design, treatment response, cancer type, dose levels, MTD, and RP2D were all collected. Dose level was categorized into 4 categories (≤40%, 41%–80%, 81%–120%, and >120% of the RP2D) and was further analyzed by class of drug. Results: A total of 175 phase I studies were identified, with a total of 7,330 patients showing a median response rate of 5% (range, 0%–83%) across trials. A total of 93 trials with 2,506 participants had response data corresponding to drug dose level. In this subset, the median response rate was 5% (range, 0%–83%) across trials. Across all participants in this subset, the response rate was 12% (57 of 491) among those in the dose range of ≤40% of RP2D, 17% (95 of 562) among those in 41% to 80% of RP2D, 23% (272 of 1,206) among those in 81% to 120% of RP2D, and 29% (71 of 247) among those in >120% of RP2D (P<.001). The response rate at ≤40% of RP2D for targeted antibody was 5%, 4% for cellular therapy, 19% for immunotherapy, and 21% for small-molecule targeted inhibitors. Conclusions: Whereas our study of published phase I trials continued to show a low response rate consistent with earlier studies, the relationship between response and dose does not always peak at 81% to 120% of RP2D anymore, likely due to the use of novel immunotherapy and targeted agents with distinct efficacy and toxicity patterns.

The relationship between response and dose in published, contemporary phase 1 oncology trials.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14583-e14583
Author(s):  
Antonious Ziad Hazim ◽  
Emerson Yu-sheng Chen ◽  
Gordon B. Mills ◽  
Vinay Prasad
Keyword(s):  
Phase I ◽  
Treatment Response ◽  
Dose Level ◽  
Phase Ii ◽  
Response Rate ◽  
Drug Dose ◽  
Phase I Trials ◽  
Recommended Phase Ii Dose ◽  
Dose Levels ◽  
The Relationship

e14583 Background: Traditional dose-escalation trial designs have changed little even as diverse classes of oncology drugs have been developed. We aimed to examine whether the association of drug dose to preliminary clinical efficacy previously established in cytotoxic chemotherapies remains true in contemporary phase I dose-escalation oncology trials. Methods: We conducted a systematic review of recent early-phase, dose-finding clinical trials of oncology drugs from November 15, 2015 to November 15, 2018 to examine the relationship between the dose of the investigational drug and objective response rate. We searched PubMed using “cancer” or “oncology” search terms and selected studies that enrolled adults with advanced cancer, determined maximum tolerated dose (MTD) and/or recommended phase II dose, and reported efficacy results by drug dose level. Trials testing combination therapies, single dose level, and non-pharmacologic therapies were excluded. Information related to the study drug, study design, cancer type, dose levels, MTD, and recommended phase II dose were all collected. Treatment response for every dose level was categorized into: complete response, partial response, stable disease, and progressive disease. Dose level was categorized into four categories: < = 40%, 41-80%, 81-120%, and > 120% of the recommended phase II dose. Results: We identified 93 trials with 2506 participants having both dose and treatment response data. Of these trials, 71 (76%) were testing targeted agents, 7 (8%) were immunotherapy, and 6 (7%) were cytotoxic chemotherapy. Median response rate across trials was 5% (range 0-83%). Among the dose range of < = 40%, the response rate was 12% (57 of 491), 41-80% was 17% (95 of 562), 81-120% was 23% (272 of 1206), and > 120% was 29% (71 of 247). Conclusions: Observed treatment response across dose levels in recent phase I trials should cause us to re-examine the toxicity-benefit ratio and influence how we design phase I trials testing novel classes of oncology drugs.

Phase I Study of AVE9633, an AntiCD33-Maytansinoid Immunoconjugate, Administered as an Intravenous Infusion in Patients with Refractory/Relapsed CD33-Positive Acute Myeloid Leukemia (AML).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4548-4548 ◽  
Author(s):  
Francis Giles ◽  
Rodica Morariu-Zamfir ◽  
John Lambert ◽  
Srdan Verstovsek ◽  
Deborah Thomas ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Disulfide Bonds ◽  
Phase I Study ◽  
Dose Range ◽  
Microtubule Assembly ◽  
Treatment Schedule ◽  
Specific Tumor ◽  
M Phase ◽  
Grade 3

Abstract AVE9633 is an immunoconjugate created by conjugation of the cytotoxic maytansinoid, DM4, to the monoclonal IgG1 antibody, huMy9-6 (average of 3.5 molecules of DM4 per antibody). The huMy9-6 antibody is a humanized version of a murine monoclonal antibody, My9-6, which is specific for the CD33 antigen expressed on the surface of myeloid cells, including the majority of cases of AML. Because CD33 has little expression outside the hematopoietic system, it represents an attractive target for antibody-based therapy in patients with AML. The humanized antibody, huMy9-6, binds to the CD33 antigen with an apparent KD in the range of 10−10 M. Maytansinoids are anti-mitotics that inhibit tubulin polymerization and microtubule assembly, inhibiting cells during the G2/M phase of the mitotic cycle. In order to link maytansinoids to antibodies via disulfide bonds, a new thiol-containing maytansinoid (DM4) was synthesized. Attachment of potent maytansinoids to an antibody via disulfide bonds provides a satisfactory stability in the bloodstream. After the conjugate is bound at the specific tumor site it is internalized and the cytotoxic agent is released within the target cell. A phase I study of AVE9633 is being conducted in patients with refractory/relapsed CD33+ AML. The study regimen consists of AVE9633 IV infusion on Day 1 of a 3 weeks cycle. To date dose levels of 15 (N=3), 30 (N=5), 50 (N=4), 75 (N=4), 105 (N=2), 200 (N=3) and 260 (N=1) mg/m2 have been investigated. Hypersensitivity reactions during perfusion were noted, requiring prophylaxis with steroids. No other AVE9633- attributable extramedullary Grade 3 AE has been observed to date. Free DM4, measured by LC/MS/MS was detectable from the 75 mg/m2 dose level; its Cmax (at the end of infusion) increased from 10 ng/mL at the 75 mg/m2 dose level to 70 ng/mL at 200 mg/m2. Neither AVE9633-associated myelosuppression nor responses have been noted. Using Flow Cytometry Assay on peripheral blasts and monocytes, total saturation and down regulation of CD33 were observed following administration of doses ≥ 30 mg/m2. AVE9633 exposure (measuring, by ELISA method, all antibodies containing at lease one molecule of DM4) increased proportionally with the administered dose in the dose range 15 to 200 mg/m2. Updated PK results and potential explanations for the lack of efficacy using this treatment schedule will be presented.

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

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1874-1874 ◽  
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Saima Dean ◽  
Peter Anglin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Oral Cyclophosphamide ◽  
Refractory Multiple Myeloma ◽  
Grade 3

Abstract Abstract 1874 Poster Board I-899 Lenalidomide (Revlimid®) and dexamethasone is an effective regimen in relapsed/refractory multiple myeloma (MM) patients (pts), with an overall response rate of 60.6% and median time to progression (TTP) of 13.4 months (Dimopoulos MA, et al, Leukemia 2009 Jul 23 [Epub ahead of print]). Oral cyclophosphamide and prednisone is an older regimen with excellent patient tolerance, and we sought to enhance the efficacy of lenalidomide by adding oral cyclophosphamide and prednisone in this phase I-II trial. The CPR regimen consisted of cyclophosphamide on days 1, 8 and 15; lenalidomide on days 1–21; and prednisone 100 mg every other day in a 28 day cycle. ASA 81 mg/day was given to all pts as DVT prophylaxis. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007–07/2009, 31 pts with relapsed/refractory MM who had not previously received lenalidomide were entered onto study. Median age was 61 (40–78) years and 61% were male. Immunoglobulin subtype was IgG in 19 pts (61%), IgA in 8 pts (26%) and light chain only in 4 pts (13%). Median number of prior regimens was 2 (1–5) and 28 pts had undergone previous ASCT, including double transplants in 6 pts. Prior therapy included thalidomide in 9 (29%) and bortezomib in 15 (48%). FISH cytogenetics were available in 13 pts; one had 13q deletion but none had t(4;14) or p53 deletion. At the time of protocol entry, median β 2-microglobulin level was 246 (92–767) nm/L, albumin 39 (34–48) g/L, creatinine 83 (50–126) μmol/L, platelet count 230 (75–337) × 109/L and ANC 2.5 (1.1–6.1) x 109/L. Protocol treatment is summarized in Table 1. Dose limiting toxicity was not observed during cycle 1 at any dose level. Grade 3–4 toxicities included thrombocytopenia in 5 pts (16%) and neutropenia in 9 pts (29%). These were managed with dose reduction and/or growth factor support. Four episodes of febrile neutropenia occurred. Other grade 3–4 non-hematologic toxicities included abdominal pain/bacteremia in 1 pt in cohort 1; hypokalemia in 1 pt in cohort 2; and DVT in 2 pts, dizziness in 2 pts and fatigue in 1 pt in cohort 3. Using the International uniform response criteria (Durie BG, et al, Leukemia 2006; 20:1467–1473), the best response was documented at a median of 6 (1–5) cycles and included the following: dose level 1 (1 CR, 2 PR); dose level 2 (1 VGPR, 2 PR); dose level 3 (5 CR, 9 VGPR, 9 PR, 1 MR and 1 stable disease). At a median follow-up (F/U) of 12 (8–21) months, 20 pts remain on study, 2 have withdrawn and 9 pts have progressed at a median of 9 (4–13) months; only 1 one has died (due to MM). We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28 day cycle with minimal toxicity; 2) the overall response rate (CR + VGPR + PR) in 31 pts to date is 93%; 3) at a median F/U of 1 year, only 9 pts (29%) have progressed; 4) longer follow-up is required to assess the TTP and survival of the CPR regimen. Disclosures: Reece: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Lenalidomide in combination with drugs other than dexamethasone. Anglin:Celgene: Honoraria. Chen:Celgene: Honoraria, Research Funding. Kukreti:Celgene: Honoraria. Mikhael:Celgene: Honoraria. Trudel:Celgene: Honoraria.

Results of a phase I trial of the proteasome inhibitor carfilzomib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7077-7077
Author(s):  
Jennifer Ann Woyach ◽  
Joseph M. Flynn ◽  
Jeffrey Alan Jones ◽  
Leslie A. Andritsos ◽  
Margaret Lucas ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase I Trial ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Lymphocytic Leukemia ◽  
Maximum Plasma ◽  
Maximal Dose

7077 Background: CLL is an incurable malignancy, and survival for patients (pts) with relapsed disease is limited. Carfilzomib (CFZ) has shown efficacy in multiple myeloma, and our group has shown significant in vitro activity in primary CLL cells. Therefore, we have undertaken a phase I trial of this agent in CLL. Methods: This is a single institution phase I trial of CFZ in pts with relapsed or refractory CLL. Primary endpoints were to determine maximal tolerated dose (MTD) and describe toxicity. Pts with CLL relapsed after at least one therapy were enrolled using a 3x3 design. CFZ was administered on the standard myeloma schedule. The first two doses were administered at 20 mg/m2 with remainder given at doses starting at 27 mg/m2 for dose level 1 with escalation to 56 mg/m2. Results: 17 pts received at least 1 dose of CFZ. 12 pts completed at least 1 cycle of therapy, with the remaining 5 experiencing PD during cycle 1. The MTD was not reached, with 3 pts accrued to each dose level to the maximal dose tested without dose limiting toxicity. Most adverse events (AE) were grade (G) 1 or 2. G3/4 AE were quickly reversible and included G3 neutropenia (4 pts), G4 neutropenia (2), G3 febrile neutropenia (1), and G3 thrombocytopenia (3). G1/2 toxicities observed in ≥ 20% of pts included anemia (10), thrombocytopenia (7), and hypocalcemia (8). Median number of cycles was 3, with 9 pts achieving stable disease after 2 cycles. Of 3 pts enrolled at maximal dose level, 2 remain on therapy after 5 and 7 months, with 1 achieving a clinical partial response. Of 5 evaluable pts, at least 50% proteasome inhibition was seen in all at 1 hour, with minimal recovery at 24 hours. PK was best characterized by a two-compartment model. Maximum plasma concentrations across all dose levels ranged from 0.81 to 8.1 uM. Across the evaluated dose range, area under the curve increased in an apparent dose-proportional manner. Conclusions: Despite relatively limited efficacy in this study, CFZ has acceptable toxicity in CLL, with no MTD identified up to 56 mg/m2. This suggests that CFZ may be better studied in CLL using a different schedule or in combination with other active agents. Clinical trial information: NCT01212380.

scholarly journals A Multicenter, Open Label Phase I/II Study of Carfilzomib, Pomalidomide and Dexamethasone in Relapsed and/or Refractory Multiple Myeloma (MM) Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1145-1145 ◽  
Author(s):  
Sara Bringhen ◽  
Valeria Magarotto ◽  
Anna Marina Liberati ◽  
Angelo Belotti ◽  
Alessandra Larocca ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Research Funding ◽  
Low Dose ◽  
Response Rate ◽  
Primary Objective ◽  
Advisory Board ◽  
Level 1

Abstract Background: Survival rates of multiple myeloma (MM) patients (pts) has improved over the past few years, but patients inevitably relapse and become more resistant to subsequent treatments. Carfilzomib and Pomalidomide were both approved for the treatment of relapsed/refractory MM (RRMM). Combinations including a proteasome inhibitor (PI) plus an immunomodulator (IMiD), such as Bortezomib-Lenalidomide-Dexamethasone (VRD) or Carfilzomib-Lenalidomide-Dexamethasone (CRD), showed a very high response rate with an acceptable toxicity. Moreover, in the CHAMPION1 study (Berenson et al Blood 2016), the weekly infusion of Carfilzomib showed to be as effective as the twice schedule. In this phase I/II study we assessed for the first time weekly Carfilzomib plus Pomalidomide and low dose Dexamethasone (wKPd) for the treatment of RRMM. Here we report preliminary results. Methods: the primary objective of the phase I part of the trial was to determine the maximum tolerated dose (MTD) of wKPd combination. The primary objective of the phase II was to determine the rate of partial response (PR). Patients with RRMM, who received 1-3 prior lines of treatments and were refractory to Lenalidomide were eligible. Treatment consisted of 28-day cycles of oral Pomalidomide at fixed dose of 4 mg on days 1-21 (1 week off), oral or intravenous (iv) Dexamethasone 40 mg on days 1,8,15,22 and iv Carfilzomib at escalating doses on days 1,8,15. Escalation started at the dose of 36 mg/m2 (0 level) and used a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. Treatment was continued until relapse or intolerance. Results: A total of 57 patients were enrolled in 6 Italian centers. Fifty-two patients could be evaluated for this analysis (5 patients did not complete the first cycle yet). The median age was 62 years with a median time from diagnosis of 4 years. 17/39 (44%) of patients were considered high risk according to cytogenetic abnormalities [at least one among t (4;14) t (14;16) and deletion chromosome 17 (del17) detected by FISH]. In the phase I of the trial 15 patients were enrolled. The first 3 patients at the dose level 0 of Carfilzomib did not experience any DLT. In the next cohort with Carfilzomib 20/45 mg/m2 a G3 hypertension and a sudden death occurred. According to the protocol, 3 more patients were enrolled at dose level 0: 1 patient experienced G3 atrial fibrillation, 2 patients ≥ G3 hypertension. Considering the serious adverse events (SAEs) occurred, the trial was temporary stopped to evaluate the benefit of continuing the study. All the DLTs were cardiologic and occurred in patients with a prior history of cardiac disease. As per protocol, they were evaluated with ECG and echocardiogram before the enrolment and were considered eligible for the study. The safety committee established new procedures for the evaluation of cardiac function of potentially eligible patients, including 24 h continuing pressure monitoring before the enrolment and serial measurement of blood pressure during and after Carfilzomib infusions. Six more patients were enrolled at dose level -1 (Carfilzomib 20/27 mg/m2) and none experienced a DLT. The MTD was established at dose level -1 with Carfilzomib 20/27 mg/m2, Pomalidomide 4 mg and Dexamethasone 40 mg. In the phase II portion of the trial, 42 patients were enrolled. Considering both phase I and II portions of the study, the most frequent drug related, grade ≥ 3 AEs were hematologic (65% of neutropenia and 13% of thrombocytopenia) and cardiologic (17%, mainly hypertension). We recorded only 4% of infection and ≥ G3 peripheral neuropathy. The overall response rate (ORR) of phase I/II portions was 58% (30/52) including 25% (13/52) of ≥ very good partial remission (VGPR). The ORR of high risk patients was 44% (7/16) including 19% (3/16) of ≥ VGPR. With a median follow-up of 10 months, median progression free survival (PFS) was 9.5 months and the median overall survival was not reached. Conclusions: This is the first phase I/II trial that combined weekly Carfilzomib with Pomalidomide and Dexamethasone. This combination was highly effective in RRMM. After a median follow-up of 10 months, wKRd showed a double median PFS in comparison with Pomalidomide-low dose dexamethasone (Sanmiguel et al Lancet Oncology 2013): 9.5 vs 4 months respectively, confirming the efficacy of combining a PI with an IMiD. An updated analysis will be presented at the meeting. Disclosures Bringhen: BMS: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Amgen: Other: ADVISORY BOARD; Mundipharma: Other: ADVISORY BOARD; Karyopharm: Other: ADVISORY BOARD. Larocca:Celgene: Honoraria; Janssen-Cilag: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria. Gaidano:Karyopharm: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Oliva:Amgen: Honoraria; Celgene: Honoraria; Takeda: Honoraria. Sonneveld:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Boccadoro:Janssen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Abbivie: Honoraria; Mundipharma: Research Funding; SANOFI: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding.

Phase I-II study of high-dose epirubicin in advanced non-small-cell lung cancer.

1992 ◽  
Vol 10 (2) ◽  
pp. 297-303 ◽  
Author(s):  
R Feld ◽  
R Wierzbicki ◽  
P L Walde ◽  
F A Shepherd ◽  
W K Evans ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Small Cell Lung Cancer ◽  
Dose Level ◽  
Cell Lung Cancer ◽  
Response Rate ◽  
Small Cell ◽  
High Dose ◽  
Small Cell Lung ◽  
Febrile Episodes

PURPOSE A phase I multicenter trial was performed to determine the maximum-tolerated dose (MTD) of epirubicin, given on 3 consecutive days every 3 weeks to previously untreated patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS After appropriate staging and a baseline multiple-gated angiogram (MUGA) scan, at least four patients were entered at each dose level, starting at 35 mg/m2 of epirubicin given intravenously (IV) daily for 3 days (105 mg/m2) and escalating by 5 mg/m2 per injection in each dose level (15 mg/m2 per course). Epirubicin was administered up to a maximum dose of 60 mg/m2/d for 3 days (180 mg/m2). The MTD was determined to be 55 mg/m2/d for 3 days (165 mg/m2) after treating a total of 35 (33 assessable) patients. Nadir granulocyte counts and associated febrile episodes comprised the dose-limiting toxicity, but there were no treatment-related deaths. A phase II trial was performed using a dose of 50 mg/m2/d for 3 days (150 mg/m2) every 3 weeks with no dose escalation, but with dose reduction for toxicity as required. A total of 30 patients were entered onto this phase of the study. RESULTS The major toxicity, as in the phase I trial, was neutropenia with five febrile episodes, again with no treatment-related deaths. An overall response rate of 12 of 63 (19%) was noted in the combined patient population of the phase I-II trial, with 95% confidence intervals of 10% to 31%. When the response rate was analyzed by histology, only one of 17 (6%) patients with squamous histology, as compared with 11 of 46 (24%) with non-squamous histology, responded, but this did not reach statistical significance (P = .15). CONCLUSIONS High-dose epirubicin is tolerable and is an active single agent in NSCLC. It should be combined with relatively nonmyelosuppressive agents such as cisplatin to try to obtain higher response rates and extend the survival in this disease.

scholarly journals A Phase I Study of Lenalidomide and Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2318-2318
Author(s):  
Elizabeth A. Griffiths ◽  
William Brady ◽  
Wei Tan ◽  
Carlos E Vigil ◽  
James E. Thompson ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Phase I Study ◽  
Response Rate ◽  
Single Agent ◽  
Grade 3 ◽  
Acute Myeloid ◽  
Intermediate Dose

Abstract Background: Relapsed/refractory (r/r) Acute Myeloid Leukemia (AML) remains a therapeutic challenge. Although cytarabine arabinoside (AraC) is the most active drug, constituting the backbone of a majority of r/r regimens, the benchmark response to therapy remains a dismal 17 to 20% (Burnett, Wetzler et al. JCO, 2011.). The immunomodulatory drug lenalidomide (Len), is approved by the Food and Drug Administration for multiple myeloma and myelodysplasia and has demonstrated activity as a single agent in AML at doses as high as 50 mg for 21 days (d) of a 28 d cycle (Blum et al, JCO, 2010.). Based upon this activity profile we developed a phase I study to evaluate the safety and tolerability of Len in combination with AraC in patients with r/r AML. Methods: Eligible patients were older than 18 years(y), had r/r AML with an Eastern Cooperative Oncology Group performance status better than 2 and adequate renal and hepatic function. Patients were excluded for active CNS disease, uncontrolled infections, congestive heart failure, adrenal insufficiency, anti-cancer therapy within 14 d of enrollment, or prior exposure to Len. All enrolled patients had to practice appropriate contraception. Patients received AraC 1.5 g/m2/d over 3 hours on d 1-5 of a 28 day cycle, with a plan for standard 3+3 Len dose escalation. Initial patients received Len 25 mg on d 6-10 (n= 3), subsequent patients received doses between 25 and 10 mg (dose de-escalation) on d 6-26 with 2 d of rest prior to the next cycle. Following induction, patients who had residual AML (>5%) could receive a second identical course of therapy, provided they demonstrated an improvement in blast percentage relative to baseline. Patients who achieved CR received maintenance with Len 10 mg/d continuously. A 12 patient expanded cohort was enrolled at the maximum tolerated dose (MTD) to assess efficacy. Responses were assessed by International Working Group Criteria for AML (Cheson B et al. JCO, 2003.). Patient Characteristics: Fifty-one patients were consented and 45 were treated on study, 32 of these were evaluable for response, all patients were evaluated for toxicity. Approximately half the patients were female (20/45). The median age was 66 y (range 33-82) and median WBC 2.42x109/L (range 0.18-63.15). Four patients (8%) had an antecedent hematological disorder. By European LeukemiaNet criteria 2 patients (4%) had favorable risk disease, 8 (18%) were Int-1, 12(27%) were Int-2 and 11 (24%) were adverse risk; 12(27%) patients were not evaluable by ELN due to lack of karyotype or molecular data from diagnosis. Twelve patients had primary refractory AML. Results: The MTD for Len given on d 6-26 in combination with AraC at 1.5 g/m2/d x 5 d was 10 mg. Dose de-escalation from the starting dose of 25 mg on this schedule was required due to excess toxicity. The most commonly observed non-hematologic drug related adverse events seen on the study (all < grade 2 unless indicated) were nausea, increased liver function tests (>grade 3), rash (grade >3), hypokalemia (> grade 3) and fatigue. At the 25 mg dose level the dose limiting toxicity was rash, while patients enrolled at the 15 mg dose level experienced dose limiting elevation in LFTs, fatigue and bleeding. Five patients achieved a CR (16%), 5 demonstrated CRi (16%) and there were 3 hematological improvements (HI) for an overall response rate (CR+Cri+HI) of 41% (13/32). The median overall survival (OS) (95% confidence interval) for patients treated on study was 5.8 (2.5, 10.6) months and disease free survival was 3.4 (2.3, 6.2) months. Conclusions: Although prior interesting data support the activity of single agent high dose Len in r/r AML, our single institute phase I study of intermediate dose AraC followed by Len was associated with marked skin and other toxicities at the Len 25 mg dose level, precluding dose escalation to the historically more active 50 mg dose. The CR rate in this study was not dissimilar to previously reported responses with single agent or combination AraC based regimens. Issues of dose and schedule for this combination may have had a significant impact on the potential benefit for these two drugs in combination. Nevertheless, the overall low CR rate from this study does not suggest any superiority for this combination in comparison with the historical single agent response rate for intermediate dose AraC in r/r AML. Disclosures Griffiths: Celgene, Incyte and Alexion: Honoraria; Astex Pharmaceuticals: Research Funding. Wang:Incyte: Speakers Bureau; Immunogen: Other. Wetzler:MedPace: Consultancy; Bristol Myers Squibb: Research Funding; Jazz Pharmaceuticals: Consultancy; Sigma Tau: Consultancy; Amgen: Honoraria; Novartis: Honoraria; Teva: Honoraria; Plexus: Consultancy; Celgene: Research Funding.

Pomalidomide Therapy for Myelofibrosis: Analysis of Results From Three Consecutive Clinical Trials

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1759-1759 ◽  
Author(s):  
Kebede Begna ◽  
Animesh Pardanani ◽  
Ruben A. Mesa ◽  
William J Hogan ◽  
Mark R. Litzow ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Phase Ii ◽  
Response Rate ◽  
Single Agent ◽  
Costal Margin ◽  
Median Response ◽  
Long Term Treatment

Abstract Abstract 1759 Background: Pomalidomide is a second generation IMiDsÒ immunomodulatory drug that has been shown to be active in the treatment of myelofibrosis (MF)-associated anemia (J Clin Oncol 2009; 27: 4563; Leukemia 2011;25: 301). In the current sponsor-independent analysis, we report long-term follow up data on patients from the Mayo Clinic who had participated in three consecutive clinical trials using single agent pomalidomide for MF. Methods: From May 2007 to January 2010, 94 patients with MF (including primary and post-polycythemia/essential thrombocythemia) were enrolled in three consecutive phase I and II clinical trials involving pomalidomide with or without prednisone. Eight two patients who received only single agent pomalidomide constitute the study population for the current study. Follow up information was updated in July, 2011. Results: Among the 82 study patients, 19 were included in a phase I dose escalation study (2.5-3.5 mg/day), 58 in a phase II low-dose single agent pomalidomide study (0.5 mg/day), and 5 in a phase II randomized study (2 mg/day). Median age was 67 years and 63 (77 %) patients were red blood cell transfusion dependent at study entry. Forty-five (55%), 24 (29%), 7 (9%), and 2 (2%) patients remained on pomalidomide therapy for at least 6, 12, 24, and 36 months, respectively (Table 1). The overall anemia response rate per IWG-MRT criteria was 27% (22/82). Response occurred in the first 6 months in 21 (96%) of the 22 responders. The median time for response was 2.3 months (range, 1–10). The median response duration was 16.5 months (2–40). The anemia response rate in patients with spleen size palpable at less than 10 cm below the costal margin was 44 % (17/39) vs. 10 % (4/39) in those whose spleen was palpable at or above 10 cm (p=0.002). The anemia response rate was twice as likely in JAK2 mutated versus non-mutated cases (30% vs 15% p=0.2). Anemia response rate was also higher in patients with at least 50% increase in absolute basophil count during the first month of therapy: 39% (19/49) vs 6% (2/32) p=0.001). The anemia response rate was not significantly affected by karyotype, transfusion need or leukocyte count. Among the anemia responders (n=22), 3 (14%) relapsed in the first 12 months; relapse was more likely in the presence of baseline leukocytosis (p=0.006). Among the 24 patients who took pomalidomide for at lease 12 months, grade 1 sensory neuropathy developed in 4 (16%) patients. Conclusion: Anemia response to pomalidomide therapy in myelofibrosis often occurs in the first 6 months of treatment and is more likely to occur in the presence of JAK2V617F and absence of marked splenomegaly. Long-term treatment with pomalidomide might be associated with sensory peripheral neuropathy in a subset of treated patients. Disclosures: No relevant conflicts of interest to declare.

Azacitidine (AZA) Combined with Idarubicin in Higher Risk MDS - Results of a Phase I/II Study By the Groupe Francophone Des Myelodysplasies (GFM)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2884-2884 ◽  
Author(s):  
Marie Sebert ◽  
Aspasia Stamatoullas ◽  
Thorsten Braun ◽  
Jacques Delaunay ◽  
Benoît de Renzis ◽  
...  
Keyword(s):  
Phase I ◽  
Research Funding ◽  
Response Rate ◽  
Univariate Analysis ◽  
Cytogenetic Response ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Median Response ◽  
Ventricular Ejection Fraction ◽  
Significant Difference

Abstract Background: Hypomethylating agents, especially AZA, have become the reference treatment of higher risk MDS, but the median survival of about 2 years obtained with AZA remains modest, and must be further improved. In addition, AZA yields only about 30% of marrow responses (including CR+PR+marrow CR). Intensive chemotherapy combining Idarubicin (IDA) and AraC yields 30 to 50 % CR in higher risk MDS (Beran and all, cancer 2001) and IDA, as single agent, induces about 30% CR in elderly AML patients (Carella, haematologica 1990). We designed a phase I/II study evaluating the safety and efficacy of the combination of AZA and IDA (1 day during each AZA cycle) in higher risk MDS patients (NCT01305135). Methods: Main Inclusion criteria were: (1) IPSS int-2 or high MDS, or CMML with WBC < 13 G/l and marrow blasts > 10%, or AML with 20-30% marrow blasts (2) Age ≥ 18 years (3) Performance Status (PS) <=2 (4) no prior treatment, except ESAs. Patients received AZA 75 mg/m2/d SC x7d every 4 weeks combined, on day 8 of each cycle (for the first 9 cycles), with IDA 5 mg/m2 (IV) in a first cohort of 10 patients, escalated to 10 mg/m2 IV in a second cohort of 10 patients, followed by an extension study in 21 patients with the IDA 10 mg/m2 schedule. The primary endpoint of the study was response after 6 cycles according to IWG 2006 criteria. Results: Between Dec 2010 and Jan 2014, 41 patients (from 13 centers) were enrolled, including 13 women and 28 men with a median age of 74 years [IQR 70; 76]. At inclusion, WHO classification was RCMD in 1 pt, CMML in 2 pts, RAEB-1 in 10 pts, RAEB-2 in 13 pts, AML in 12 pts and unclassified MDS in 3 pts. Median marrow blast % was 9.5 [IQR: 6-19.9] and karyotype according to IPSS was favorable in 12 (29%), intermediate in 9 (22%) and unfavorable in 18 pts (44%) (2 cytogenetic failures). IPSS was int-2 and high in 56% and 44%, respectively. PS was 0 in 39%, 1 in 55% and 2 in 6% pts. 10 patients received 5 mg/m2 of idarubicin (cohort 1) and 31 received 10 mg/m2 (cohort 2). 375 cycles of AZA were administered (219 of them with AZA+IDA, as IDA was used only for the first 9 cycles), with a median number of 6 cycles/patient (median 6 in the IDA 5 mg/m2 cohort and 4 in the 10 mg/m2 cohort (p=0.9). Of the 41 patients enrolled, 20(48.8%, 95%CI: 32.9-64.9) achieved response (6 CR, 7 PR, 4 mCR and 3 stable disease with HI) with no difference between the two cohorts (50% vs 48%) and a marrow response rate (CR + PR + mCR) of 41,5%. Thirteen of the 22 patients with abnormal karyotype were evaluable for cytogenetic response: 5 achieved cytogenetic response (4 complete, 1 partial), 1 in cohort 1 and 4 in cohort 2. With a median follow up of 14 months, 9 of the 20 responders had relapsed. Median response duration was 11 months [3.2-42.7], with no difference between the two cohorts. Median OS was 14.3 months [IC95%: 12.5; NA] and 2y OS was 24.8%, with no significant difference between the 2 cohorts (p=0.43). By univariate analysis no baseline parameter including gender, karyotype, marrow blast %, IPSS and IDA dosage (5 or 10 mg/m2), had any significant impact on response or survival. 45 SAEs were reported in 26 patients, including febrile neutropenia (n=25), bleeding (n=7) and 2 non-clinically significant reductions in left ventricular ejection fraction (1 transient, and 1 persisting without symptoms). The number of infections per cycle [9/85 (10%) in the IDA 5 mg/m2 arm and 38/281 (14%) in the IDA 10 mg/m2 arm] and the number of bleeding events (9% vs 17%) did not significantly differ between the two cohorts. Conclusion: In our experience, Idarubicin (on day 8 of each cycle) can be combined to Azacitidine without any additional toxicity. The marrow response rate obtained with the combination (41.5%) may be higher than with AZA alone. We are currently comparing in higher risk MDS patients this AZA-IDA combination versus AZA alone (and other combinations of AZA with other drugs) in a prospective randomized GFM trial. Disclosures Sebert: Celgene: Research Funding. Fenaux:Celgene: Research Funding.

Phase I/II study of ABI-007 as first line chemotherapy in advanced non-small cell lung cancer (NSCLC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7105-7105 ◽  
Author(s):  
N. A. Rizvi ◽  
C. Azzoli ◽  
V. Miller ◽  
K. Ng ◽  
J. Fiore ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Dose Level ◽  
Response Rate ◽  
Single Agent ◽  
Stage Iv ◽  
Sensory Neuropathy ◽  
Phase 2 ◽  
Grade 3 ◽  
Ecog Ps

7105 Background: ABI-007 is a 130-nm albumin-bound form of paclitaxel. This study was designed to determine (1) the MTD and DLTs of ABI-007 in patients with stage IV chemotherapy-naive NSCLC and (2) the efficacy and safety of ABI-007 at the MTD. Methods: Eligibility requirement included ECOG PS 0–1, adequate organ function and sensory neuropathy ≤ grade 1. No prior chemotherapy for metastatic disease was allowed. Prior EGFR TKI therapy was allowed. ABI-007 was administered on days 1, 8, and 15 every 28 days (IV over 30 min. without premedication). In the phase I portion, 3 dose levels were studied (100, 125 and 150 mg/m2) and in the phase 2 portion, 40 patients were treated at the MTD. Results: 50 patients received ABI-007; the median age was 70 yo and 76% of patients were ≥ 65 yo. No DLTs were observed at the 100 and 125 mg/m2 dose level. However at the 150 mg/m2 dose level 2/6 patients had a DLT (febrile neutropenia and sensory neuropathy, respectively) during cycle 1 such that the MTD was exceeded. The 125 mg/m2 dose level was identified as the MTD and expanded to 40 patients in the phase 2 portion of this study. Toxicity and efficacy data is presented for the phase 2 portion. Ten patients (25%) had received prior neoadjuvant or adjuvant chemotherapy and 5 (13%) had received prior gefitinib or erlotinib. Sensory neuropathy was the most frequent toxicity with grade 2 and 3 toxicity occurring in 8% and 15% of patients. Grade 2 and 3 fatigue was observed in 8% and 13% of patients. Grade 3 and 4 neutropenia occurred in 10% and 3% of patients with no febrile neutropenia observed. Response was assessed by RECIST. One CR and 14 PRs were observed for an overall response rate of 15/40 (38%). The median survival was 10.3 months. Conclusions: The MTD for ABI-007 administered over 30 min. on days 1, 8, and 15 every 28 days was 125 mg/m2. No hypersensitivity reactions were observed and no premedication was given. In the phase 2 portion, a 38% response rate and 10.3 month survival was observed. Non-hematologic toxicities were primarily sensory neuropathy and fatigue. Myelosuppression was minimal and no febrile neutropenia was observed. Further development of ABI-007 in NSCLC is warranted based on the encouraging single agent activity observed in this study. [Table: see text]

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