Tipifarnib (ZARNESTRATM in Previously Untreated Poor-Risk AML of the Elderly: Updated Results of a Multicenter Phase 2 Trial.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 874-874 ◽  
Author(s):  
Jeffrey E. Lancet ◽  
Jason Gotlib ◽  
Ivana Gojo ◽  
Eric J. Feldman ◽  
Lawrence Morris ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Response Rate ◽  
Response Rate ◽  
Median Number ◽  
Hospitalization Rate ◽  
Phase 2 ◽  
Overall Response ◽  
Poor Risk ◽  
Phase 2 Trial ◽  
Multicenter Phase

Abstract Farnesyltransferase inhibitors (FTI) make up a novel class of anti-cancer agents that competitively and selectively inhibit farnesyl protein transferase. Early trials of the orally bioavailable non-peptidomimetic FTI tipifarnib (ZARNESTRATM, Johnson & Johnson PRD) demonstrated both clinical responses and excellent tolerability in patients with poor-risk or refractory acute myeloid leukemia (AML). (Karp, et al. Blood97:3361, 2001). We herein report updated results of a multicenter phase 2 trial of tipifarnib in an elderly, previously untreated poor-risk AML population who refused or were deemed unfit for conventional induction chemotherapy. Tipifarnib was administered orally in the outpatient setting at a dose of 600 mg BID for 21 days, followed by a 1–3 week recovery period. Up to 4 cycles of tipifarnib were permitted in patients with complete responses (CR). The primary endpoint was overall response rate (CR + PR). Secondary endpoints included toxicity rates, measurement of markers of farnesylation (HDJ-2) in bone marrow cells, measurement of signaling intermediates ERK and AKT, and RNA microarray expression patterns. Accrual to the trial is complete. 170 patients have been enrolled, 148 of whom are evaluable for response (AML=160; high-risk MDS=4; high-risk CMML=6). The median age was 73 years (range 34–85), and 76 patients (45%) were age = 75. M/F ratio was 2:1. An unfavorable karyotype and/or antecedent MDS was present in 47% and 79% of patients, respectively. The median number of cycles received was 1, and the median number of days of drug received was 36 days. Dose reductions were implemented in 38% of patients, more commonly in cycles subsequent to cycle #1. The overall response rate (CR + PR) was 34%. CR occurred in 18% of patients. Responses were evenly distributed across study centers. In patients ≥ 75 years, the overall response rate was 30% (CR 20 %). Median CR duration was 6.4 months (range 1.5–11+ months). Median overall survival was 5.6 months for all patients. CR patients had a median survival of 14.4 months, with 63% alive at 12 months. In non-responders, median survival was 3.1 months. The incidence of grade = 3 tipifarnib-related non-hematologic adverse events was 43%, comprised mainly of infectious and gastrointestinal complications. The hospitalization rate for tipifarnib-related toxicity was 18% (median duration: 12 days). The death rate from tipifarnib-related toxicity at 6 weeks was 5%. Microarray analysis of pre-and post-treatment bone marrow samples is being performed to identify both predictive and pharmacodynamic gene markers of response to tipifarnib. In summary, tipifarnib is a novel outpatient treatment with activity in previously untreated poor-risk AML. The low hospitalization rate may reflect the low incidence of severe non-hematological toxicity.

Response Rates of Phase 2 and Phase 3 Trials of Decitabine (DAC) in Patients with Myelodysplastic Syndromes (MDS).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2515-2515 ◽  
Author(s):  
Hussain I. Saba ◽  
Michael Lübbert ◽  
P.W. Wijermans
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Median Duration ◽  
Response Rate ◽  
Response Rates ◽  
Median Number ◽  
Phase 2 ◽  
Phase 3 ◽  
Overall Response ◽  
Number Of Cycles

Abstract Background: MDS is characterized by ineffective hematopoiesis, resulting in cytopenias with dysplastic morphology of peripheral blood cells and bone marrow. Decitabine (Dacogen™ DAC) is a cytosine analog that reverses aberrant DNA methylation, leading to re-expression of silenced tumor suppressor genes. Due to the requirement for DNA synthesis and subsequent demethylation, decitabine may require prolonged administration to achieve maximum benefit. Overall response rates (ORR) (CR+PR) from 1 pivotal Phase 3 (D-0007) and 3 supportive Phase 2 trials (91–01, 95–11 and 97–19) in patients with intermediate and high risk MDS receiving DAC are being presented. Methods: The Phase 2 trials were open-label and single-arm, with a minimum of 4 treatment cycles and a maximum of 8 cycles, while the D-0007 was a 1:1 randomized comparison of DAC plus supportive care (SC) vs. SC alone, with a maximum of 10 cycles of therapy. The D-0007 study design dictated that patients be removed from therapy following 8 cycles of decitabine if CR was not achieved, and 6 cycles in the absence of PR. Patients who maintained a CR for 2 cycles were removed from therapy. Results: A total of 271 unique patients were exposed to DAC in the studies (n= 89 in D-0007, n=29 in 91–01, n = 66 in 95–11, n = 87 in 97–19). Patients receiving DAC had similar demographics and disease characteristics in all trials. Responses were observed in all IPSS and FAB subgroups. The percent of patients classified as intermediate-2 and high risk (according to the International Prognostic Scoring System) in the Phase 3 trial was 69% vs. 72% in the Phase 2 trials. By intent-to-treat analysis, the ORRs were 45%, 26%, and 26% respectively, for the Phase 2 trials. These results were corroborated in the Phase 3 trial, where the response rates were evaluated according to the more robust International Working Group MDS criteria, following a blinded, centralized bone marrow review. The D-0007 overall response rate was 17% for DAC (9% CR, 8% PR) vs. 0% for SC (p<0.001). Responses were durable, lasting a median of 266 days. The 95–11 and 97–19 response rates were also centrally reviewed, while 91–01 responses were investigator-assessed. In the 91–01 trial, the ORR was 45% (28% CR, 17% PR) with a median duration of response of 217 days, the 95–11 ORR was 26% (21% CR, 5% PR) with a median duration of 250 days, and the 97–19 ORR was 26% (22% CR, 5% PR) with a median duration of 146 days. Hematologic improvement (HI) was also evaluated according to varied criteria in conjunction with the response rates in all 4 studies; 12 patients (13%) had HI in D-0007, 2 patients (7%) in 91–01, 8 patients (12%) in 95–11, and 13 patients (15%) in 97–19. The D-0007 trial design dictated that patients who maintained a CR for 2 cycles be removed from therapy. As a result, the median number of cycles delivered was 3, with only 48% of patients receiving ≥4 cycles. In the Phase 2 studies, the median number of cycles is clearly higher (median 4), with the majority of patients receiving at least 4 cycles and approximately one-third of patients receiving ≥6 cycles. Conclusion: While response rates of ≥17% were demonstrated in these trials, the optimization of hypomethylating agents for maximum efficacy is very likely to include prolonged therapy, which may correlate with increases in response rate and duration.

scholarly journals Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma

Blood ◽  
2016 ◽  
Vol 127 (21) ◽  
pp. 2561-2568 ◽  
Author(s):  
Rachid C. Baz ◽  
Thomas G. Martin ◽  
Hui-Yi Lin ◽  
Xiuhua Zhao ◽  
Kenneth H. Shain ◽  
...  
Keyword(s):  
Overall Response Rate ◽  
Response Rate ◽  
Phase 2 ◽  
Overall Response ◽  
Multicenter Phase ◽  
Oral Regimen ◽  
Phase 2 Study ◽  
Key Points

Key Points PomCyDex results in a higher overall response rate than pomalidomide and dexamethasone. PomCyDex is an effective, all oral regimen for refractory myeloma patients.

SDX-105 Demonstrates a High Response Rate as a Single-Agent with Acceptable Safety in Rituximab-Refractory, Relpased Indolent or Transformed Non-Hodgkin’s Lymphoma (NHL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2480-2480 ◽  
Author(s):  
Jonathan Friedberg ◽  
Philip Cohen ◽  
Robert O. Kerr ◽  
K. Sue Robinson ◽  
Andres Forero-Torres ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dose Reduction ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Mitotic Catastrophe ◽  
Hematologic Toxicity ◽  
Overall Response ◽  
Cell Death Pathway ◽  
Grade 3

Abstract SDX-105 (Treanda™, Bendamustine HCl) is an alkylating agent that may exert its anti-tumor activity via mitotic catastrophe, an apoptosis-independent cell-death pathway, as well as, through apoptosis. Its cytotoxic potency is unattenuated in chemotherapy-resistant lymphoma cell lines. We initiated a multi-center Phase II trial to investigate the safety and efficacy of SDX-105 in patients with rituximab-refractory, relapsed indolent or transformed B cell NHL. Patients must have pathologically-confirmed disease that has been demonstrated to be rituximab-refractory (no response or progression within 6 months) or must be intolerant of rituximab. Other requirements include measurable disease, adequate renal, hepatic and bone marrow function (ANC ≥1K/mm3, platelet ≥ 100K/mm3, except in cases of &gt;50% NHL in bone marrow), up to 3 prior chemotherapies, and no prior allogeneic transplant. Patients receive SDX-105, 120 mg/m2 IV over 30–60 min, days 1 and 2, every 21 days. Grade 4 hematologic toxicity during a cycle results in dose reduction for subsequent cycles (to 90 mg/m2 and then to 60 mg/m2). Patients achieving stable disease or better after 6 cycles may receive up to 6 more cycles. 49 patients have been accrued to date with data available on the first 15 patients. The median age is 69 yrs (range 47–84), 47% male, median 6 yrs since diagnosis with NHL. Histologies: 10 follicular (6 Grade 1, 3 Grade 2, 1 Grade 3), 2 SLL, 1 marginal zone and 2 transformed NHL. Other features include: 93% Stage III/IV, 20% with B symptoms, 87% with extranodal disease, median 2 prior chemotherapies with 40% not responding to last chemotherapy. 4 patients have required dose reduction to 90 mg/m2 and 2 patients have withdrawn prior to completing 6 cycles due to treatment-associated toxicity. The current overall response rate (ORR) based upon best response in the intent-to-treat population is 80% (CR/CRu 20%, PR 60%). Overall 73% of patients experienced a related non-hematologic adverse event (AE), of which 20% were Grade 3 and 0% Grade 4. The most frequent AEs were nausea (40%), vomiting (27%), fatigue (33%), anorexia (20%), and constipation (20%). Alopecia was not observed. Grade 3 or 4 hematologic toxicity was seen in 53% (neutropenia), 20% (thrombocytopenia), and 13% (anemia) of patients. 4 patients experienced serious AEs, including 1 patient with baseline renal insufficiency who died on study from renal failure and pulmonary edema; other events include admissions for fever and anemia, urinary tract infection, and dehydration. Based upon these preliminary findings, SDX-105 demonstrates a high overall response rate with acceptable hematologic toxicity and modest non-hematologic toxicity in a relapsed lymphoma patient population, many of whom are refractory to rituximab-chemotherapy combinations. An additional study evaluating the combination of SDX-105 and rituximab in patients with relapsed indolent NHL who are rituximab-sensitive is also ongoing.

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.

Gemcitabine in Combination with Oxaliplatin (GEMOX) As a Salvage Regimen in Patients with Relapsed/Refractory Hodgkin's Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1517-1517 ◽  
Author(s):  
Evren Ozdemir ◽  
Alma Aslan ◽  
Alev Turker ◽  
Ibrahim Barista ◽  
Ayse Kars
Keyword(s):  
Hodgkin’S Lymphoma ◽  
Overall Response Rate ◽  
Response Rate ◽  
Median Number ◽  
Hodgkin's Lymphoma ◽  
Hematological Toxicity ◽  
Hematologic Toxicity ◽  
Refractory Disease ◽  
Salvage Regimen ◽  
Overall Response

Abstract This study's objective was to evaluate the efficacy and safety of gemcitabine in combination with oxaliplatin (GEMOX) as a salvage regimen in patients with relapsed or refractory Hodgkin's lymphoma. Twenty-five patients were enrolled. All patients had received ≥ 2 prior chemotherapy regimens, had an ECOG performance status ≤ 2 and had adequate organ function. Patients received intravenous gemcitabine (1000 mg/m2) and oxaliplatin (100 mg/m2) on days 1 and 15, every 4 weeks. The median age was 29 years (range, 18-64) and 16 (68%) were male. Twenty-one (84%) had primary refractory disease (n=13) or relapsed within 12 months after initial therapy (n=8). All had previous platinum-based salvage chemotherapy (ICE, 23; DHAP, 2). Ten patients (40%) had relapsed/refractory disease following autologous stem cell transplantation (SCT). None had previous brentuximab vedotin treatment. Twenty-one (84%) patients were refractory or progressive on the last treatment. Median number of previous lines of chemotherapy was 2 (range, 2-4). Median number of GEMOX cycles administered to the patients was 3 (range, 2-6). Treatment response was evaluated with PET-CT before and 2-3 cycles after treatment, and those patients who demonstrated a response continued to receive a maximum of 6 courses of GEMOX or bridged to SCT. Of 25 patients, 2 (8%) had complete response, 9 (36%) had partial response and the remaining patients had refractory/progressive disease with an overall response rate of 44%. Seven of the 10 patients who had relapsed/refractory disease after autologous SCT achieved a response (CR, 2; PR, 5). The median time to progression for responding patients was 3 months (range, 1-40 months). One patient is disease free for 40 months. Three patients were successfully bridged to SCT (autologous, 2; allogeneic, 1). Main toxicity was hematological. Grade ≥ 3 hematologic toxicity occurred in 10 patients: thrombocytopenia (36%), neutropenia (16%) and anemia (8%). Among these, 7 had previous autologous SCT. One patient had grade 4 neutropenia and thrombocytopenia. Treatment cycle postponed in 6 patients without dose reduction because of hematological toxicity. Seven patients (28%) needed G-CSF support. One patient developed febrile neutropenia. No treatment-related deaths occurred. GEMOX was shown to be an effective salvage regimen in patients with relapsed/refractory Hodgkin's lymphoma, producing an overall response rate of 44%. It is an active regimen in patients who had relapsed/refractory disease after autologous SCT. Although, the median PFS time was short, some patients can be bridged to SCT and some can get long-term PFS. Hematological toxicity was common, especially in patients with previous autologous SCT. Disclosures Off Label Use: Gemcitabine in Hodgkin's Lymphoma Oxaliplatin in Hodgkin's Lymphoma.

Phase I/II study of R-ICE (rituximab-ifosfamide-carboplatin-etoposide) with lenalidomide (R2-ICE) in patients with first-relapse/primary refractory diffuse large B-cell lymphoma (DLBCL) in academic and community cancer research united (ACCRU) network.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS8073-TPS8073 ◽  
Author(s):  
Francis Guerra-Bauman ◽  
Betsy LaPlant ◽  
William R. Macon ◽  
Thomas E. Witzig ◽  
Umar Farooq ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Cell Transplant ◽  
Phase 2 ◽  
Overall Response ◽  
Lymphoma Therapy

TPS8073 Background: Response rates to salvage immunochemotherapy in patients with DLBCL relapsing after or refractory (R/R DLBCL) to front line therapy remain unsatisfactory. Lenalidomide (Len) has significant single agent activity in relapsed/refractory DLBCL. The addition of lenalidomide (Len) days 1-7 to rituximab plus ifosfamide-carboplatin-etoposide (RICE) was shown to be feasible with promising efficacy in phase 1b study (Feldman T, et al. BJH, 2014). We developed phase I/II study to evaluate the safety and efficacy of the addition of Len (extended to 14 day schedule) to RICE (R2-ICE) for R/R-DLBCL patients who are candidates for stem cell transplant. Methods: The phase I portion was designed to determine the maximally tolerated dose Len in combination with RICE using the standard cohort 3+3 design. The escalation dose levels were 15 mg and 20 mg daily x 14 days. Prophylactic aspirin and growth factor support is mandatory. After 2 cycles of therapy response is evaluated with a PET/CT scan; the responding patients are eligible for 1-2 additional cycles of R2ICE as a bridging before HDC/SCT. The estimated overall response rate for two cycles of R-ICE in R/R DLBCL to RCHOP was estimated to be approximate 45%. We hypothesize that the addition of lenalidomide in the relapse setting could increase the overall response rate by approximately 20%. The one-stage design with an interim analysis being utilized in phase 2 requires 45 evaluable patients (one sided alpha = 0.09, power 90%). For Phase I, all types of B-cell lymphomas were eligible. For phase II portion only DLBCL patients are eligible per central pathology review. Other eligibility criteria include: received one line of previous anti-lymphoma therapy, ≥ 2 weeks from completion of prior anti-lymphoma therapy, candidate for HDC and SCT, adequate organ (creatinine clearance ≥ 60ml/min by Cockcroft-, total bilirubin ≤ 2 × ULN) and bone marrow function (ANC) ≥1500/mm3; platelet count ≥75,000/mm3). The use of steroids and/or rituximab up to 1 week prior to registration for management of symptoms is allowed. 9 patients cleared phase 1 without DLT and dose of 20 mg days 1 -14 was recommend for phase 2 part (RP2D) of the study. The phase 2 study passed interim futility analysis and accrual continues. Correlatives include cell of origin by Nanostring, Myc/bcl2 expression and by FISH and minimal residual disease. PET scans are centrally reviewed including metabolic tumor volume. Clinical trial information: NCT02628405 .

Results of an open-label multicenter phase 2 trial of lenalidomide monotherapy in refractory mycosis fungoides and Sézary syndrome

Blood ◽  
2014 ◽  
Vol 123 (8) ◽  
pp. 1159-1166 ◽  
Author(s):  
Christiane Querfeld ◽  
Steven T. Rosen ◽  
Joan Guitart ◽  
Madeleine Duvic ◽  
Youn H. Kim ◽  
...  
Keyword(s):  
Disease Burden ◽  
Overall Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Open Label ◽  
Phase 2 Trial ◽  
Multicenter Phase ◽  
Key Points ◽  
Flare Reaction

Key Points Lenalidomide is effective in refractory advanced cutaneous T-cell lymphoma, with an overall response rate of 28%. Patients demonstrate a transient flare reaction in skin, blood, and/or lymph nodes that may be associated with improvement in disease burden.

scholarly journals Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial

2021 ◽  
Author(s):  
Daniel J. DeAngelo ◽  
Deepti H. Radia ◽  
Tracy I. George ◽  
William A. Robinson ◽  
Albert T. Quiery ◽  
...  
Keyword(s):  
Overall Response Rate ◽  
Response Rate ◽  
Systemic Mastocytosis ◽  
Remission Rate ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Severe Thrombocytopenia ◽  
Phase 2 ◽  
Overall Response ◽  
Primary Endpoints

AbstractAdvanced systemic mastocytosis (AdvSM) is a rare hematologic neoplasm driven by the KIT D816V mutation and associated with poor survival. This phase 1 study (NCT02561988) evaluated avapritinib (BLU-285), a selective KIT D816V inhibitor, in patients with AdvSM. The primary endpoints were the maximum tolerated dose, recommended phase 2 dose and safety of avapritinib. Secondary endpoints included overall response rate and changes in measures of mast cell burden. Avapritinib was evaluated at doses of 30–400 mg once daily in 86 patients, 69 with centrally confirmed AdvSM. Maximum tolerated dose was not reached, and 200 mg and 300 mg daily were studied in dose-expansion cohorts. The most frequent adverse events observed were periorbital edema (69%), anemia (55%), diarrhea (45%), thrombocytopenia (44%) and nausea (44%). Intracranial bleeding occurred in 13% overall, but in only 1% of patients without severe thrombocytopenia (platelets <50 × 109/l). In 53 response-evaluable patients, the overall response rate was 75%. The complete remission rate was 36%. Avapritinib elicited ≥50% reductions in marrow mast cells and serum tryptase in 92% and 99% of patients, respectively. Avapritinib induced deep and durable responses, including molecular remission of KIT D816V in patients with AdvSM, and was well tolerated at the recommended phase 2 dose of 200 mg daily.

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