Preliminary Report from an Exploratory Phase II Trial with Plitidepsin (Aplidin®) in Patients with Refractory/Relapsed Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2569-2569 ◽  
Author(s):  
M. V. Mateos ◽  
J. Blade ◽  
F. Prosper ◽  
J. J. Lahuerta ◽  
R. Garcia-Sanz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase Ii ◽  
Proteasome Inhibitors ◽  
Median Number ◽  
Hematological Toxicity ◽  
Second Stage ◽  
Liver Transaminases ◽  
Previously Treated ◽  
Grade 3 ◽  
Number Of Cycles

Abstract Introduction and objectives : Plitidepsin is a cyclic depsipeptide originally isolated from the marine tunicate, Aplidium albicans. It appears very potent against multiple myeloma (MM) cells. Specifically, it was observed that it was active against a broad panel of 35 human MM cell lines, which included MM cells resistant to conventional anti-MM agents and novel agents (i.e. thalidomide, bortezomib). Plitidepsin also induced cell death in primary MM tumor cells freshly isolated from patients resistant to thalidomide or its analogs and/or proteasome inhibitors. Phase I has been completed exploring 4 different schedules of administration. Muscle and liver (transaminases and/or alkaline phosphatase) toxicities were the main DLTs. Hematological toxicity was not observed at the recommended dose. The aim of this trial was to explore the activity of plitidepsin in patients with previously treated refractory/relapsed MM. Material and Methods: This is a non-randomized two-stage Phase II, multicenter, clinical and pharmacokinetic trial, with Aplidin® (APLD) 5 mg/m2 as a 3 h intravenous infusion every 2 weeks, with antiemetic and antihistaminic prophylaxis. In the first stage 16 patients evaluable for efficacy were included. At least one response was requested in order to proceed with the second stage, in which a total of 37 patients will be included. Results: Between June’04 and June’05, 19 patients have been enrolled and data are available for 18 patient (7 men and 11 women, median age was 65.7y, range 48–82). Patients were previously relapsed/refractory. Prior treatments included: stem cell transplantation 64.7%, thalidomide 35.28% and bortezomib 17.64%. The median previous chemotherapy lines received were 3, range 1–6. The APLD median number of cycles received 4, range 1–16. Thirteen patients are currently evaluable for efficacy. One patient (7.7%) achieved a partial response (PR) with a 70% reduction in M-component lasting 8 months. Stable disease lasting between 3–5 months was observed in 3 patients (23.0%). In 2 patients (15.38%) a stabilization lasting 2.5 months was stated and the remaining 7 patients (53.8%) progressed. NCI-CTC grade 3–4 related toxicities were reported for n=17 patients and were mainly fatigue in 2 patients (11.8%), myalgia in 1 patient (5.9%), elevation of CPK in 1 patient (5.9%) and transient transaminases increase in 9 patients (52.9%). Significant hematological toxicity did not occurred in spite of 2 patients included and treated with thrombopenia grade 3–4 and 2 patient with neutropenia grade 3. Conclusions: First stage data shows that APLD presents hints of activity in patients with refractory/relapsed MM, with acceptable toxicity profile, thus meeting the criteria for proceeding to second stage recruitment. The absence of significant hematological toxicity is a well known feature of this drug and is being confirmed in this trial.

A Phase I/II Study of Bortezomib and Low Dose Intravenous Melphalan (BM) for Relapsed Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2555-2555 ◽  
Author(s):  
Rakesh Popat ◽  
Heather E. Oakervee ◽  
Nicola Foot ◽  
Samir Agrawal ◽  
Patricia Smith ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Progressive Disease ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Median Number ◽  
Overall Response ◽  
Grade 3 ◽  
Number Of Cycles

Abstract Background: Bortezomib as a single agent has known efficacy in the treatment of relapsed multiple myeloma. The overall response rate (CR+PR+MR) was 35% in the SUMMIT study and 46% in the APEX study. In-vitro studies including our own have demonstrated potent synergy with other chemotherapeutic agents such as melphalan. It therefore follows that responses to bortezomib may be further improved by the combination of such drugs. Aims: The primary objectives of this Phase I/II study was to assess the safety, tolerability and response rates in patients with relapsed multiple myeloma; secondary objectives being time to progression (TTP) and overall surival (OS). Methods: This was a multi-centre, non-randomised trial for patients with relapsed myeloma. Patients received bortezomib 1.3mg/m2 on days 1,4,8 and 11 of each 28 day cycle with melphalan on day 2 at increasing dose levels. This was initially at 10mg/m2, but due to cytopenias subsequently at 2.5 and 5mg/m2 (levels 1a, 1 and 2) and we plan to escalate to 7.5mg/m2. Up to 8 cycles were given with dexamethasone added for stable or progressive disease after 4 or 2 cycles respectively. Responses were determined by EBMT criteria. Results: To date, 18 patients have been enrolled (12 male 6 female; median age 60 [range 44–73]; median number of prior therapies 3 [range 1–5] of which 17 have had at least one autologous stem cell procedure with high dose melphalan; 10 prior thalidomide and 2 prior bortezomib). 12 patients received melphalan at 10mg/m2 but due to unacceptable delays predominantly due to thrombocytopaenia, subsequent treatment levels commenced at 2.5mg/m2. The median number of cycles completed thus far is 4 (range 0–8) and of the 16 evaluable, the overall response rate (CR+PR+MR) across all treatment levels was 50% rising to 75% following the addition of dexamethasone as per protocol. At level 1a (melphalan 10mg/m2 ,N=12, median number of cycles completed =5) the best responses (with dexamethasone as indicated) were: 1CR, 1 VGPR, 5 PR, 2 MR; at level 1 (melphalan 2.5mg/m2, N=4) 1 PR, 2 MR (after 2 cycles only). The median time to any response was 1 cycle (range 1–3 ). Three patients have progressive disease, but the median TTP and OS have not yet been reached (median follow-up 3 months). Non-haematological toxicities have been modest with 7 SAEs reported of which only 1 was possibly drug related (myocardial infarction), and 4 episodes of Grade 3 neuropathy (2 resulting in study withdrawal). The commonest grade 3–4 haematological toxicity was thrombocytopaenia (N=10) complicated by bleeding in one patient, followed by neutropenia (N=6). Summary: The combination of bortezomib and intravenous melphalan can be given safely to patients with relapsed multiple myeloma and dose escalation is ongoing. Myelosupression was the commonest grade 3–4 adverse event. A response rate of 50% was seen, which was further improved to 75% with the addition of dexamethasone. This combination may therefore result in higher responses than single agent bortezomib in heavily pretreated patients.

A Phase II Open-Label, Multi-Center Study of Anti-CCR4 Monoclonal Antibody Mogamulizumab (KW-0761) in Patients with Previously Treated Peripheral T-Cell Lymphoma(PTCL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1763-1763 ◽  
Author(s):  
Pier Luigi Zinzani ◽  
Bertrand Coiffier ◽  
John Radford ◽  
Dolores Caballero ◽  
Paul Fields ◽  
...  
Keyword(s):  
T Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Median Number ◽  
Advisory Board ◽  
Japanese Study ◽  
Duration Of Response ◽  
Previously Treated ◽  
Grade 3

Abstract Background CC chemokine receptor 4 (CCR4) is the receptor for macrophage-derived chemokine (MDC/CCL22) and thymus activation-regulated chemokine (TARC/CCL17). CCR4 is expressed on tumour cells in approximately 30-65% of patients with PTCL (Ogura, 2014). PTCL-NOS patients who are CCR4 positive have been reported to have a poorer prognosis compared to CCR4 negative patients (Ishida T CCR 2004). Mogamulizumab (KW-0761) is a defucosylated, humanized, IgG1 Mab with enhanced antibody dependent cellular cytotoxicity, that binds to CCR4. Mogamulizumab was evaluated in both phase 1 and 2 trials in Japanese patients. A phase II trial in PTCL and cutaneous T-cell lymphoma (CTCL) patients (Ogura, 2014) reported an overall response rate (ORR) of 35% in patients who relapsed after last systemic therapy (ORR was 34% in PTCL), leading to its approval in Japan in patients with previously treated CTCL and PTCL, in addition to its first indication, previously treated adult T-cell leukemia-lymphoma. Here we report the preliminary results of a European phase II trial of mogamulizumab in patients with relapsed/refractory PTCL. Methods A multi-center phase II study of mogamulizumab monotherapy was conducted to determine efficacy, safety and immunogenicity in patients with CCR4+ PTCL. The primary endpoint was ORR and secondary endpoints included duration of response, progression-free survival (PFS) and overall survival (OS). At least 34 evaluable patients were needed to detect a significant improvement over 15% assuming 80% power and a 0.0240 alpha significance level (assumes 35% ORR for alternative). Patients received mogamulizumab once weekly for 4 weeks and subsequently once every 2 weeks until progressive disease (PD) or unacceptable toxicity at a dose of 1.0 mg/kg. Responses were assessed every 8 weeks according to IWG criteria (Cheson et al 2007). Results Based on a preliminary analysis of the data, a total of 38 patients received at least one administration of mogamulizumab and were evaluable for safety analysis; (Male/female 23/15 ;Median age 58.5 years (range 19-87)). Three patients are still ongoing in the study (1 complete response (CR) and 2 stable disease (SD)). ECOG performance status at baseline was 0 (32%); 1 (29%); 2 (39%) and 92% of patients had stage III (32%) or IV (61%) disease. The median number of prior treatments was 2 (range 1-8). Only 17 patients (49%) responded to the last treatment administered prior to study entry. The median number of mogamulizumab administrations was 6 (range 1-32). The majority of adverse events (AEs) were CTCAE grade 1-2. Skin rash related to drug was observed in 32% of patients (12/38) and related AEs > grade 3 occurred in 32% (12) of patients. Infusion related reactions occurred in 3 patients (2 were CTCAE grade 2 and 1 was grade 3). Thirty-five patients were evaluable for efficacy. The ORR rate was 11% and the stable disease rate was 34% with a SD or better rate of 46%. The response by histological subtype is specified in the table below. The median duration of response (including SD) is 2.9 months. The median PFS is 2.1 months. Two patients (ALCL-ALK-neg and PTCL-NOS) proceeded to allogeneic SCT. Although the ORR in this study was less than seen in the Japanese study, the PFS was comparable. There were differences in patient population/study conduct between the Japanese study and this study, respectively, which included: inclusion of only relapsed patients (100% vs 49%), ECOG PS 2 (0% vs 39%) and response assessments (after 4 and 8 weeks versus 8 weekly from week 8). Conclusions Based on preliminary data, mogamulizumab demonstrates a SD or better rate of 46% and an ORR of 11% with an acceptable safety profile in this phase II study of heavily pre-treated relapsed/refractory PTCL patients. TableBest Overall Response by Histological subtypeNo of subjectsCR/PR n (%)SDn (%)>SD n (%)PTCL-NOS152* (13%)6 (40%)8 (53%)AITL122 (17%)3 (25%)5 (42%)TMF301 (33%)1 (33%)ALCL-ALK neg402 (50%)2 (50%)ALCL-ALK pos1000Efficacy Evaluable Subjects354 (11%)12 (34%)16 (46%) *One patient had CR by CT scan but did not have bone marrow done for confirmation of CR Disclosures Zinzani: Sandoz: Consultancy; Celgene International Sàrl: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; MundiPharma International Ltd: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Pfizer Inc: Advisory Board Other, Honoraria, Speakers Bureau; Takeda Pharmaceutical Company Limited: Advisory Board Other, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Advisory Board Other, Honoraria; GlaxoSmithKline: Advisory Board, Advisory Board Other, Honoraria; Gilead: Advisory Board, Advisory Board Other; Bayer AG: Advisory Board Other, Consultancy. d'Amore:CTI Life Sciences: Speakers Bureau; Mundipharma: Speakers Bureau; Takeda/Seattle Genetics : Speakers Bureau; Sanofi-Aventis: Research Funding; Amgen: Research Funding; Roche: Research Funding; Kyowa-Kirin: Advisory Board Other. Haioun:Roche: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Pfizer: Honoraria; Janssen: Honoraria. Morschhauser:Genentech: Honoraria; Bayer: Honoraria; Spectrum: Honoraria; Mundipharma: Honoraria; Gilead: Honoraria.

A phase I clinical study of biweekly carboplatin and gemcitabine in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12024-12024
Author(s):  
P. Kumar ◽  
M. Keshtgarpour ◽  
H. Kumar ◽  
A. Dudek
Keyword(s):  
Performance Status ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Hematological Toxicity ◽  
Ecog Performance Status ◽  
Primary Tumors ◽  
Grade 3 ◽  
Number Of Cycles ◽  
Tumor Types ◽  
Dose Levels

12024 Background: Carboplatin (CBDCA) and gemcitabine (GEM) in combination is used commonly in lung cancer and is administered on a 21 day cycle. The purpose of this study was to determine the maximum tolerated dose (MTD) of CBDCA and GEM administered on a biweekly schedule and to assess safety and efficacy of this schedule. Methods: GEM was given intravenously (IV) over 30 minutes followed by CBDCA also given IV over 30 minutes. This combination was given on day 1 every 2 weeks. The dose levels examined are shown in the Table . A total of 26 patients were studied (18 male, 8 female) with median age of 56 (range 41–83 years); ECOG performance status of 24 patients were 0 (5), 1 (16), 2 (2), 3 (1); prior chemotherapy ranged from 0 to 4 regimens; median number of cycles administered per patient was 3 (range 1–9) with a total of 81 cycles. The primary tumors were lung (11), melanoma (4), head and neck (3), squamous cell penile/toe (2), bladder (2), kidney (1), gastric (1), esophageal (1) and ovary (1). Results: No DLTs were seen in any of these patients and the MTD was not reached. Delay in treatment was seen in total of 6 cycles due to myelosuppression and 1 cycle due to nausea and anorexia. Grade 3/4 hematological toxicity rates: anemia - 3/81 cycles (3.7%), neutropenia - 20/81 cycles (25%), and thrombocytopenia - 4/81 cycles (5%). Non-hematological toxicity was mild. The median time to progression was 40 days (range 4–133) and of 18 evaluable patients partial response or stable disease was seen in 7 (38.8%). Conclusions: Even at maximum tested dose of GEM at 2000 mg/m2 and CBDCA at AUC of 3.0, this schedule is well tolerated. Hematological toxicity such as neutropenia and thrombocytopenia was minimal. We plan to study this schedule of GEM and CBDCA in appropriate tumor types in combination with biologic agents. [Table: see text] [Table: see text]

Weekly bortezomib in the treatment of patients (pts) with previously treated multiple myeloma: A phase II trial of the Minnie Pearl Cancer Research Network

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7547-7547 ◽  
Author(s):  
F. A. Greco ◽  
D. R. Spigel ◽  
J. H. Barton ◽  
C. Farley ◽  
M. T. Schreeder ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Research Network ◽  
High Dose ◽  
Weekly Schedule ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
Previously Treated ◽  
Grade 3

7547 Background: Bortezomib, administered on a twice-weekly schedule, is now a standard part of treatment for patients with multiple myeloma. Weekly bortezomib schedules have shown activity in other cancer types, and are more convenient than twice weekly schedules. In this multicenter, community-based phase II trial, we evaluate the feasibility, toxicity, and efficacy of weekly bortezomib in pts with previously treated multiple myeloma. Methods: Eligibility criteria included a diagnosis of multiple myeloma treated with 1 or 2 previous systemic regimens (only 1 if first-line therapy included high-dose therapy); ECOG PS 0–2; creatinine < 2.0 mg/dL; WBC ≥ 3000/μL; ANC > 1000/μL; platelets ≥ 50,000/μL; no peripheral neuropathy > grade 1; informed consent. All pts received bortezomib 1.6mg/m2 IV on days 1, 8, 15, and 22 of each 5-week cycle. Pts were reevaluated at 10-week intervals; treatment continued for 8 cycles (40 weeks) or until myeloma progression. Results: Between 5/04 and 12/05, 37 pts entered this trial. Pt characteristics: median age 70 years; male/female, 20/17; 24 pts (65%) had received 2 previous regimens (previous high dose therapy, 2 pts); elevated β-2 microglobulin, 27 pts (73%). Of 26 pts evaluated, 13 pts (50%) had major responses, 11 pts (42%) stable disease, and 2 pts (8%) had progression. After a median follow-up of 7 months, projected median PFS is 9.6 months; overall survival at 1 year is 81%. Weekly bortezomib was well tolerated by most pts. Grade 3/4 toxicities included fatigue (21%), diarrhea (11%), neutropenia (7%), thrombocytopenia (4%), all others < 5%. No grade 3/4 neuropathy occurred. Only 1 pt required bortezomib dose reduction during treatment, and 2 pts discontinued treatment because of toxicity (myelosuppression, 1; fatigue/dehydration, 1). Conclusions: Weekly bortezomib is a convenient, well tolerated treatment for pts with previously treated multiple myeloma. Overall response rates with this schedule are similar to those previously reported with the standard twice-weekly schedule. Further followup is necessary to better evaluate the duration of response and the incidence of cumulative toxicities. [Table: see text]

A randomized phase II study of perifosine (P) plus imatinib for patients with imatinib-resistant gastrointestinal stromal tumor (GIST)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10563-10563 ◽  
Author(s):  
A. P. Conley ◽  
D. Araujo ◽  
J. Ludwig ◽  
V. Ravi ◽  
B. L. Samuels ◽  
...  
Keyword(s):  
Phase Ii ◽  
Median Number ◽  
Blurred Vision ◽  
Imatinib Resistance ◽  
Choi Criteria ◽  
Grade 3 ◽  
Exon 11 ◽  
Number Of Cycles ◽  
Ecog Ps ◽  
Advanced Gist

10563 Background: P inhibits activation of the Akt pathway which results in apoptosis and block cancer cell proliferation. Since AKT is a molecule downstream of Kit, its inhibition may overcome Kit-dependent imatinib resistance. We performed a phase II trial to assess antitumor activity of perifosine in patients with advanced GIST who were refractory to imatinib mesylate. Methods: Pts with Kit(+) advanced GIST who have PD on IM were eligible. Pts continued their current dose of IM and were randomized to one of two dosing schedules of P (Arm A: 100 mg p.o. qd x 28 + IM or Arm B: 900 mg [300 mg p.o tid] qweekly + qd IM). A Bayesian approach was utilized to assess a target response rate or 20% with an unacceptable toxicity rate of 15% or less. Response was measured at q8 wk intervals by RECIST and Choi criteria. The primary endpoint was to determine the efficacy of P with IM in pts with advanced GIST with PD while receiving IM. Results: From 8/2005 to 7/2008, 41 pts were accrued. After 1 pt exclusion and 2 cross-overs, 22 pts were in Arm A and 18 pts in Arm B. Median age was 58 (range, 32–82), 51% were male, and median ECOG PS was 1. The most common primary site of disease and metastasis was the stomach (29%) and liver (66%), respectively. KIT genotype was available for 22 pts(54%); 5(12%) WT, 13(32%) exon 11 mutations, and 4(10%) exon 9 mutations. The median number of cycles was 2 (range, 1–24). By Choi and RECIST, 30 pts(73%) and 36 pts(87%) were available for response, respectively. No CR was identified but the PR rate was 4/36 (11%) by Choi (4 PR, 9 SD) and 0/36 (0%) by RECIST (16 SD). 4/5 (80%) of pts with WT KIT appeared to benefit (Choi: 1 PR, 3 SD; RECIST: 4 SD). Median PFS and OS for 40 pts were 2.2 months and 18.3 months. No difference in PFS was noted for the 2 schedules. Toxicity was assessed in 39 pts; 46 grade 3 events and 4 grade 4 events (ALT elevation, blurred vision, fatigue, and mood alteration) were noted. The most common grade 3 event was fatigue (20%). Three pts (7%) were removed from the study for toxicity (Arm A:1 pt, Arm B:2 pts). Conclusions: The addition of P to IM has minimal activity in IM-refractory GIST although its activity in GIST with WT KIT may be further investigated. No significant financial relationships to disclose.

Biweekly cetuximab and irinotecan as second-line therapy to patients with platinium-resistant gastroesophageal cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15624-e15624 ◽  
Author(s):  
J. K. Bjerregaard ◽  
K. R. Schønnemann ◽  
H. A. Jensen ◽  
L. W. Vestermark ◽  
T. P. Hansen ◽  
...  
Keyword(s):  
Phase Ii ◽  
Performance Status ◽  
Haematological Toxicity ◽  
Median Number ◽  
National Board ◽  
Line Therapy ◽  
Grade 3 ◽  
Number Of Cycles ◽  
The Cost

e15624 Background: There is no established 2nd line therapy for patients (pts) with advanced gastroesophageal (GE) cancer. In 2004, the Danish government initiated a national health programme for pts with advanced cancer. Non- proven therapy may be offered after approval by an expert panel appointed by the National Board of Health that subsequently finances the cost of treatment. This programme has had a major impact on the management of cancer pts in Denmark and has accelerated the introduction and implementation of new therapies. Inspired by the excellent results in colorectal cancer a combination of cetuximab and irinotecan (CetIri) was chosen for platinum-resistant GE cancer. While awaiting approval of a phase II protocol CetIri was offered at a single institution. We report our preliminary experience with biweekly CetIri as 2nd line therapy in pts with GE cancer. Methods: All pts had histologically confirmed GE cancer (adeno- or squamous cell carcinoma) and all pts had previously received first line platinum based therapy. Pts received CetIri (cetuximab 500 mg/m2and irinotecan 180 mg/m2day 1) every 2nd week until progression or unacceptable toxicity. Response rate was evaluated by the investigator according to RECIST every 8th week. Toxicity was prospectively evaluated according to NCIC-CTC 3.0. Results: From December 2007 to August 2008, 31 consecutive pts was treated with CetIri. Median age was 62 years (33–76). Median performance status was 1 (0–2). Localisation of primary was: Esophagus 10%, GE junction 64%, gastric 26%. Twenty-seven pts (87%) had adenocarcimona. Median number of cycles were 6 (1–21). Most important grade 2–4 toxicities were non-haematological toxicity as diarrhea (25%), nausea (21%) and vomiting (11%). Three pts (11%) had grade 3 leukopenia, 1 had febrile neutropenia. Two pts had PR. Median PFS was 3.2 months. Fourteen pts (45%) received at least 6 courses (3 month of therapy). After a median follow-up of 6 month 5 pts continue CetIri without sign of PD. Conclusions: Biweekly CetIri is a convenient and well-tolerated 2nd line regimen in pts with GE cancer. Predictive factors are needed to select which pts will benefit from therapy. A confirmatory phase II study is ongoing. [Table: see text]

Clarithromycin, pomalidomide, and dexamethasone (ClaPD) in relapsed or refractory multiple myeloma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8036-8036
Author(s):  
Adriana C. Rossi ◽  
Tomer Martin Mark ◽  
Melissa Rodriguez ◽  
Manan Shah ◽  
Ryann Quinn ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Median Number ◽  
Phase 2 ◽  
Disease Response ◽  
Vte Prophylaxis ◽  
Phase 2 Trial ◽  
Chain Analysis ◽  
Grade 3 ◽  
Number Of Cycles

8036 Background: Clarithromycin has been shown to enhance anti-myeloma activity of lenalidomide+dexamethasone in the upfront treatment of multiple myeloma (MM). Pomalidomide is an immunomodulatory agent effective in relapsed/refractory MM (RRMM). We hypothesized that clarithromycin may similarly enhance pomalidomide + dexamethasone in RRMM. We now report updated results from a phase 2 trial of ClaPD in RRMM. Methods: 73 patients with RRMM were enrolled in a single-institution phase 2 study of ClaPD. All subjects had ≥ 3 prior lines of therapy, one of which must have included lenalidomide. ClaPD is clarithromycin 500mg twice daily; dexamethasone 40mg weekly; and pomalidomide 4mg for days 1-21 of a 28-day cycle. All patients had VTE prophylaxis with aspirin. Monthly disease response evaluation included immunoelectrophoresis and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM responses. Treatment continued as tolerated until disease progression. Results: The 66 patients who completed ≥ 1 cycle of ClaPD are reported. Median number of cycles was 6 (range 1-17). Responses were progressive disease: 10%, stable disease: 21%, minimal response: 12%, partial response: 33%, very good partial response: 18%, stringent complete remission: 5%, for an overall response rate (ORR) of 56% and ≥VGPR rate of 23%. Median time to PR was 1.25 cycles (range 1-8). Median PFS was 5 months. Response and PFS were not different in patients refractory to lenalidomide (85%), bortezomib (82%), or double-refractory patients (76%). After a median follow up of 12 months,28 pts (42%) remain on study without progression and 56pts (85%) are alive. Two pts withdrew due to toxicity (1 Grade 3 fatigue, 1 Grade 4 muscular weakness). One patient withdrew consent. Conclusions: ClaPD is highly effective for heavily pre-treated RRMM, particularly in lenalidomide-refractory disesase and compares favorably to previously published Phase 2 data of Pom/Dex (ORR 56% vs 40% - Lacy et. al JCO 2009) without excess toxicity. Response to ClaPD is rapid, well tolerated, and sustained over 7 months in most subjects. These data support the clinical efficacy of pomalidomide based regimens in RRMM.

Updated results from a randomized phase II dose-ranging study of the JAK2-selective inhibitor SAR302503 in patients with myelofibrosis (MF).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7109-7109 ◽  
Author(s):  
Animesh Dev Pardanani ◽  
Catriona H. M. Jamieson ◽  
Nashat Y. Gabrail ◽  
Claudia Lebedinsky ◽  
Guozhi Gao ◽  
...  
Keyword(s):  
High Risk ◽  
Phase Ii ◽  
Median Number ◽  
Randomized Phase Ii ◽  
Night Sweats ◽  
Dose Ranging ◽  
Grade 3 ◽  
Number Of Cycles ◽  
Dose Reductions ◽  
Unacceptable Toxicity

7109 Background: We previously reported results of treating MF patients with 3 cycles of 300, 400, or 500 mg of SAR302503 (NCT01420770; Blood 2012;120:21 Abs 2837). This is a report of efficacy and safety after 6 cycles. Methods: Patients ≥18 years of age with intermediate-2 or high-risk MF and splenomegaly were eligible. SAR302503 is administered orally, once a day in consecutive 4-week cycles until disease progression or unacceptable toxicity. Spleen response (≥35% reduction in spleen volume vs baseline) was assessed by MRI/CT (blinded independent central review). Results: 31 patients were enrolled (n=10 in the 300 and 400 mg groups; n=11 to 500 mg). Risk status was balanced in all but the 300 mg group (70% high-risk). Most patients were JAK2V617F positive (90%) and blood transfusion independent (81%). Spleen response rates at the end of cycle (EOC) 6 (secondary end point) were 30% (3/10) in the 300 mg group, 60% (6/10) with 400 mg, and 55% (6/11) with 500 mg compared with EOC 3 rates of 30%, 50%, and 64%, respectively. One patient on 500 mg who had a spleen response at EOC 3 (39% reduction), but not at EOC 6 (25% reduction) had dose reductions to 200 mg due to anemia. Median number of cycles was 13 (range, 2–17) and 24 patients have been on treatment >12 months. SAR302503 reduced baseline constitutional symptoms at the EOC 3, with the greatest responses for night sweats in 14/15 patients (93%), itching 10/14 (71%), early satiety and abdominal pain, each in 10/18 (56%). Most common adverse events were anemia and diarrhea, with grade 3–4 rates of 58% and 13%, respectively. The rate of grade 3–4 thrombocytopenia was 16%. There was no grade 3–4 neutropenia. The diarrhea rate tended to decrease after the first 2 treatment cycles. There have been no reports of withdrawal syndrome after stopping SAR302503. Median JAK2V617F allele burden was 93% at baseline, 87% at the EOC 3, and 78% at EOC 6 in 19/26 patients who had available samples. The expression of 22 of 97 cytokines was significantly regulated (≥1.5 fold difference; p<0.05) after cycle 1. Conclusions: In this Phase II trial, continued treatment with SAR302503 was associated with clinically meaningful reductions in splenomegaly. Symptom data will be updated. Clinical trial information: NCT01420770.

The MEK inhibitor selumetinib ([SEL], AZD6244, ARRY-142886) plus irinotecan (IRI) as second-line therapy for KRAS-mutated (KRASm) metastatic colorectal cancer (CRC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3587-3587 ◽  
Author(s):  
Howard S. Hochster ◽  
Wells A. Messersmith ◽  
Bert H. O'Neil ◽  
Susan G. Groshen ◽  
Heinz-Josef Lenz ◽  
...  
Keyword(s):  
Phase Ii ◽  
Mek Inhibitor ◽  
Median Number ◽  
Dose Finding ◽  
Second Line ◽  
Stage Design ◽  
Line Therapy ◽  
Grade 3 ◽  
Gi Bleed ◽  
Number Of Cycles

3587 Background: There are few therapies for second-line KRASm CRC. Inhibiting downstream signal transduction may offer therapeutic options. Use of selumetinib (MEK 1/2 inhibitor; AstraZeneca) is supported by preclinical and clinical evidence. We designed a dose-finding/phase II study of IRI + SEL in KRASm CRC. Methods: Eligibility included: KRASm or BRAFm CRC with measurable disease progressing after 1st-line therapy with an oxalipatin + bevacizumab regimen; PS 0-1; acceptable organ function. Patients (Pts) were treated with IRI 180 mg/m2 iv q2w and SEL 50 or 75 mg po bid. Dose escalation was traditional 3+3 (50 mg bid SEL, then 75 mg bid). In Part B/phase II, primary endpoint was PI-determined response rate (RR) by RECIST. A Simon 2-stage design allowed expansion to 45 pts if ≥1 responses in 20 pts was seen; ≥4/45 responses would be encouraging, when compared to historical RR of 4% (and median PFS 2.5 mo) [EPIC, Sobrero 2008], with approximately 90% power to detect an ORR of 15% at the 10% alpha level (one-sided). Results: N =32 pts entered; 31 treated. Median age was 54 (27-75) yrs; 18 male and 24 Caucasian. The first 3 pts tolerated SEL 50 mg bid without DLT and the remaining 28 were treated at 75 bid. Median number of cycles on study was 3.5 and median PFS was 3.4 mo. Grade 3 AEs included (N): diarrhea 3, fatigue 2, neutropenia 2, and 1 each thrombocytopenia, enteritis, GI bleed, rash. There was one Grade 4 neutropenia. The best PI-reported response included 3 (10%) confirmed PR and 16 (52%) SD [including 1 unconfirmed PR]. 6 patients were on study for more than 6 (up to 22) months. The study was terminated early due to non-protocol considerations. Conclusions: In this small study, the RR of 10% and med PFS of 3.4 mo in pts with KRASm CRC treated with IRI + SEL in 2nd line are promising compared with prior studies in non-selected patients. MEK inhibition in KRASm CRC should be explored further. Supported in part by AstraZeneca.

BTTC08-01: A phase II study of bevacizumab and erlotinib after radiation therapy and temozolomide in patients with newly diagnosed glioblastoma (GBM) without MGMT promoter methylation.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2019-2019 ◽  
Author(s):  
Jeffrey J. Raizer ◽  
Pierre Giglio ◽  
Jethro Lisien Hu ◽  
Morris D. Groves ◽  
Ryan Merrell ◽  
...  
Keyword(s):  
Phase Ii ◽  
Median Number ◽  
Mgmt Promoter ◽  
Newly Diagnosed Glioblastoma ◽  
Post Radiation ◽  
Grade 3 ◽  
Number Of Cycles ◽  
The Brain ◽  
Worse Prognosis ◽  
Clinical Trial Information

2019^ Background: Patients (pts) with GBM with unmethylated MGMT have a worse prognosis than those with methylated MGMT. Novel approaches for this poor risk group are warranted. The Brain Tumor Trials Collaborative (BTTC) performed a phase II trial evaluating standard chemoradiation followed by bevacizumab and erlotinib in patients with MGMT unmethylated GBM. EGFR and VEGFR are upregulated during radiation suggesting that this combination could be more effective than post-radiation adjuvant temozolomide (TMZ). Methods: After informed consent, adult patients with supratentorial GBM, KPS ≥ 70 and > 1 cm2 tumor block for MGMT promoter analysis were screened. Only tumors with confirmed unmethylated MGMT promoter were enrolled. All patients received RT + TMZ and then approximately 4 weeks after RT they received bevacizumab 10 mg/kg every 2 weeks and erlotinib 150 mg/day, continuously. One cycle was 4 weeks; evaluation by MRI was every 2 cycles. Treatment continued until disease progression or intolerable adverse events. Results: 115 patients were screened; 48 were enrolled (2 unevaluable: 1 for an infratentoral GBM and 1 withdrew after 7 days of treatment) with 29 men, 17 women. Median age was 56 yrs (29-75); median KPS was 90 (70-90). The median number of cycles was 8 (2-38) with 4 patients remaining on trial at the time of analysis. Objective responses: 4 CR, 12 PR and 30 SD. Median PFS is 7.3 months (95% CI (6.4, 11)) and median OS 14.2 months (95% CI (10.7, not reached)). There were no unexpected toxicities; grade 3/4 rate < 5%. Conclusions: Adjuvant bevacizumab and erlotinib in GBM with unmethylated MGMT is well tolerated. Preliminary efficacy data is comparable with outcomes in similar unmethylated MGMT patient populations from the EORTC/NCIC and RTOG 0525 studies. Tissue correlation is being performed. Clinical trial information: NCT00720356.

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