A phase II study of erlotinib (E) and bevacizumab (B) in patients (pts) with previously untreated stage IIIB/IV non-small cell lung cancer (NSCLC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7625-7625 ◽  
Author(s):  
H. J. Groen ◽  
E. F. Smit ◽  
A. Dingemans
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Phase Ii Study ◽  
Smoking Status ◽  
Single Agent ◽  
Stage Iiib ◽  
Correlative Imaging ◽  
Unknown Reason ◽  
Grade 3

7625 Background: In advanced NSCLC, E and B either as a single agent (E) or in combination with chemotherapy (B) show improved survival. Combinations of targeted agents may prove to be effective and better tolerated than chemotherapy. Methods: This is a multi-center 2-stage phase II study (Simon's optimal design; p0=40%, p1=60%, a=0.05, β=0.20). Primary endpoint is non-progression (NPR) at 6 weeks defined by CT and FDG-PET. If 7 or less of the first 16 pts had NPR, the study would close. If 24/46 pts had NPR at 6 wks treatment would be declared to have sufficient activity for further testing. Pts (PS 0–2) with advanced non- squamous NSCLC who had received no prior chemotherapy were treated with E (150 mg/day) plus B (15 mg/kg every 21 days) until PD or unacceptable toxicity. Results: Between 30/01/06 and 08/12/06, 38 pts were included; 33 pts are evaluable for safety, 32 for efficacy. M/F 17/16; median age 59 (range 34–80); stage IIIB/IV 8/25; PS 0/1/2: 16/13/4; smoking status: current/former/never 12/17/4. Treatment-related adverse events (all grades) were: rash (32%); diarrhea (18%); hemorrhage (2.6%); hypertension (2.7%); and thrombosis (2.7%). Grade 3/4 events were rash (9.9%); thrombosis (1.8%); diarrhea (0.9%); and hypertension (0.9%). Six pts withdrew early from the study: 2 due to toxicity (trombosis and mucositis); 2 due to death (1 death for unknown reason, 1 due to pneumonia); 2 for treatment unrelated reasons. Six pts had E dose reductions due to toxicity. Five pts had delays of less than 2 wks before receiving B. Percentage of NPR at 6 weeks is 75% (24/32). The median follow-up: 6.3 months (95% CI 3.5–9.2). Median TTP: 5.5 months (95% CI 1.9 - 9.2), At time of analysis 22/33 patients are alive, 17 patients are without PD. Conclusions: E + B regimen is well tolerated, with a low rate of grade 3/4 adverse events and no unexpected toxicities. The primary endpoint has already been met. Updated results including correlative imaging studies will be presented. No significant financial relationships to disclose.

Results of a Feasibility and Phase II Study on Bortezomib (BTZ) in Pediatric Multiply Relapsed or Refractory Acute Lymphoblastic Leukemia: Complete Hematological Responses with a Modestly Intensive Regimen Including BTZ

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2290-2290
Author(s):  
Gertjan Kaspers ◽  
Denise Niewerth ◽  
Satianand Ramnarain ◽  
Andishe Attarbaschi ◽  
André Baruchel ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Clinical Research ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Phase Ii Study ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Research Support ◽  
Grade 3 ◽  
Intensive Regimen

Abstract Prognosis of refractory and relapsed ALL is poor and its improvement requires the introduction of novel agents with a new mechanism of action. Bortezomib (BTZ) as proteasome inhibitor is such an agent, and has been shown to be safe as single agent in phase I studies in children with either solid tumors (Blaney 2004) or leukemias (Horton 2007). Recently, Messinger (2012) reported in a single-arm study that BTZ can be combined safely with vincristine (VCR), dexamethasone (DXM), pegylated asparaginase (PEG-ASP) and doxorubicin and that the combination was remarkably effective in B-cell precursor ALL. BTZ has been reported to sensitise malignant cells to other agents, both in vitro for leukemias as well as for multiple myeloma patients in vivo. In patients with ALL, the sensitizing effect of BTZ regarding the efficacy of glucocorticoids (GC) has not been addressed yet. Considering the lack of any clinical experience with BTZ in children, we developed a European multicenter feasibility and phase II study in refractory or relapsed ALL, in which all patients receive BTZ, with day 8 peripheral blast count as primary endpoint. The study is performed in compliance with the Declaration of Helsinki. Patients are randomised for BTZ to be administered “early”, or “late”. Bortezomib is then given as iv push for 4 doses at 1.3 mg/m2/dose, thus in group “early” on days 1, 4, 8 and 11 and in group “late” on days 8, 11, 15 and 18. In addition, all patients receive DXM (10 mg/m2/day in 3 doses for 2 weeks, orally or iv) and VCR (1.5 mg/m2/dose with a maximum of 2 mg as 1-hour infusion on days 8 and 15), as well as one intrathecal administration of methotrexate (MTX, dose age-adjusted) on day 1. No ASP and no anthracycline is given. Cycles can be repeated in case of a good response. Eligible patients have 2nd or greater relapsed ALL, 1strelapsed ALL after allogeneic stem cell transplantation (allo-SCT) in CR1, or refractory first relapsed ALL, and bone marrow (BM) involvement and at least 100 leukemic cells per µl blood. Exclusion criteria include symptomatic CNS leukemia. It is planned to evaluate 24 fully evaluable randomised patients. This analysis, not being an official interim-analysis and not evaluating the primary endpoint of the study, focusses on haematological responses with this modestly intensive regimen. BM M1 indicates <5% blasts, M2 5-15% and M3>15% blasts. Between October 2010 and March 2014, a total of 21 eligible patients with information on response and/or toxicity after cycle 1 has been enrolled, 11 boys and 10 girls, median 9.8 years of age (range, 1.2 – 17.5). Most had second relapsed ALL (n=11), others first relapsed ALL following allo-SCT in CR1 (n=8) or refractory first relapsed ALL (n=2). Regarding efficacy, 17 patients were evaluable (1 patient no material received, 2 patients discontinued treatment due to toxicity, and 1 patient had early progression which led to treatment discontinuation). Day 22 BM showed M1 in 5, M2 in 6, and M3 in 6 patients. There was no relation between day 22 BM status and the administration of BTZ being early or late. There was no association between response and disease status, being either refractory or relapsed, although numbers are small. Two patients with a relapse after allo-SCT achieved BM M1, as well as 3 patients with a second or subsequent relapse. Four patients (23.5%) achieved hematological remission after cycle 1, while 11 out of 17 patients (65%) had a good initial response (day 22 BM M1 or M2). A total of 10 patients received a 2ndcycle and 5 out of them achieved a complete remission, 4 of whom already had a day 22 BM M1. Eight out of 21 (38%) patients suffered from grade 3 and/or 4 toxicity during cycle 1, and most frequently reported were pain (n=4), peripheral neuropathy and fatigue (n=2 each). After 2 cycles, grade 3/4 toxicity was reported in 3 out of 10 patients: one with peripheral neuropathy, one with peripheral neuropathy, haemorrhage and hematuria, and one with raised ALAT. Future analyses will focus on sensitisation to GC by BTZ and on the efficacy of BTZ in relation to PK and PD. Meanwhile, BTZ in combination with VCR, DXM and intrathecal MTX is effective in a significant subset of pediatric relapsed and refractory ALL, and repetitive cycles could be given in several children without undue toxicity. This research is financially supported by the Dutch Foundation Children Cancer-free (clinical research support) and by Janssen Pharmaceuticals (clinical research support and free drug). Disclosures Baruchel: Janssen-Cilag: Consultancy.

scholarly journals Phase II Study of Venetoclax in Combination with Obinutuzumab and Bendamustine in Patients with High Tumor Burden Follicular Lymphoma As Front Line Therapy (PrECOG 0403)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 814-814
Author(s):  
Craig A. Portell ◽  
Opeyemi Jegede ◽  
Nina D. Wagner-Johnston ◽  
Grzegorz S. Nowakowski ◽  
Christopher D. Fletcher ◽  
...  
Keyword(s):  
Adverse Events ◽  
Follicular Lymphoma ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Single Agent ◽  
Tumor Burden ◽  
Type I ◽  
High Tumor Burden ◽  
Grade 3

Abstract Background: Chemoimmunotherapy is considered standard initial therapy for follicular lymphoma (FL) with high tumor burden (HTB). Obinutuzumab and Bendamustine (OB) with maintenance Obinutuzumab (mO) is considered a standard therapy for the frontline treatment of HTB FL (GALLIUM, Marcus et al, NEJM 2017). Venetoclax (VEN), an oral BCL2 inhibitor, is an attractive target in FL given the high BCL2 expression; though single agent activity has been disappointing (Davids et al. JCO 2017). BCL2 inhibition is thought to be synergistic with chemotherapy. Thus, the PrE0403 study evaluated the OB-VEN combination in frontline HTB FL. Here we present end of induction (EOI) outcomes. Methods: The primary objective of this Phase II study was to estimate the complete remission (CR) rate at EOI. Potential participants must have had a histologically confirmed diagnosis of FL grade 1, 2, or 3a with HTB defined by GELF or high risk defined by FLIPI-1 criteria. They must have had adequate performance status and organ function. Notably, creatinine clearance must have been ≥50 mL/min. Participants must have not had prior treatment for FL. Eligible participants were treated with Bendamustine IV 90 mg/m2 Day (D) 1 & 2, Obinutuzumab IV 100 mg D1, 900 mg D2, 1000 mg D8 and D15 of Cycle (C) 1 then D1 of each cycle, and VEN 800 mg orally daily D1-10 every 28 days for 6 total cycles. Due to a high rate of laboratory tumor lysis syndrome (TLS) during C1 in the first 21 patients, VEN was removed from C1 and given in C2-6 only. Participants with a CR at EOI were treated with mO IV 1000 mg D1 every 8 weeks for 2 years. Those with a partial response (PR) or stable disease (SD) were treated with mO as well as VEN 800 mg orally daily for 2 years. Pneumocystis jiroveci Pneumonia (PJP) and antiviral prophylaxis was required as was G-CSF support. Response was assessed via Lugano Criteria at EOI including PET/CT and bone marrow assessment. Adverse Events (AEs) were evaluated using CTCAE v5.0. To be considered promising, OB-VEN should improve the null hypothesis CR rate of 50% (OB) to 65%. With an 85% power and a one sided 15% type I error, 56 participants would be needed with an estimated 51 eligible. Support for the study was from Genentech, Member of the Roche Group. Results A total of 56 participants were enrolled and treated between 12/2017 and 11/2020; baseline characteristics are listed in Table 1. TLS was closely monitored in C1 and 8/21 participants developed TLS when VEN was administered in C1; 0/35 when it was not. However, monitoring for TLS in C1 became less stringent when VEN was not administered. Treatment related Grade ≥3 toxicities occurred in 47/56 participants (83.9%) with serious adverse events in 31 of 56 (55.5%). Atypical infections were seen; there was one treatment related death on study due to cytomegalovirus (CMV) encephalitis as well as PJP pneumonia which occurred after induction C6. Enrollment was temporarily suspended and CMV monitoring was implemented with no further occurrences. Another participant receiving mO later developed BK virus nephropathy following mO C6 and now requires ongoing hemodialysis. Another was diagnosed with Respiratory Syncytial Virus pneumonia 30 days after C6 and later PJP pneumonia after C2 of mO. Common (incidence &gt;10%) AEs during induction are listed in Table 2. 45 of 56 (80.4%) participants were able to receive all 6 cycles of OB-VEN. CR was seen in 41 of 56 participants (73.2%, 2 sided 95% Confidence Interval (CI) 59.7-84.2%) at the EOI. 30 participants (53.5%) went onto maintenance. With a median follow up of 20.9 months, estimated 2 year Overall Survival (OS) and Progression-Free Survival (PFS) (90% CI) is 94.4% (82.4-98.3%) and 85.8% (68.8-93.9%) respectively. Conclusions This Phase II study of OB-VEN in untreated HTB FL showed high CR rate and met its primary endpoint with early signs of prolonged PFS. Laboratory TLS was identified but it was unclear if attributed solely to VEN, as baseline laboratory TLS rate for OB is unknown. The rate of Grade ≥3 AE of 83.9% (compared to 69% for OB in GALLIUM, Hiddeman JCO 2018) and the observation of opportunistic infections including CMV encephalitis, PJP pneumonia and BK nephropathy, suggests the combination is highly immunosuppressive. Therefore, while the study met its primary outcome, the combination of OB-VEN at 800 mg for 10 days, plus mO, does not have an acceptable risk/benefit profile. Participants will continue to be followed for efficacy and safety during the maintenance phase. Figure 1 Figure 1. Disclosures Portell: Acerta/AstraZeneca: Research Funding; SeaGen: Research Funding; Pharmacyclics: Honoraria; Xencor: Research Funding; Aptitude Health: Honoraria; BeiGene: Honoraria, Research Funding; Abbvie: Research Funding; TG Therapeutics: Honoraria, Research Funding; Kite: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Morphosys: Honoraria; Targeted Oncology: Honoraria; Genentech: Research Funding; VelosBio: Research Funding. Nowakowski: MorphoSys: Consultancy; Incyte: Consultancy; Kymera Therapeutics: Consultancy; TG Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Nanostrings: Research Funding; Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Celgene/Bristol Myers Squibb: Consultancy, Research Funding; Zai Labolatory: Consultancy; Daiichi Sankyo: Consultancy; Bantham Pharmaceutical: Consultancy; Curis: Consultancy; Karyopharm Therapeutics: Consultancy; Selvita: Consultancy; Ryvu Therapeutics: Consultancy; Kyte Pharma: Consultancy. Cohen: Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo, BeiGene, Adaptive: Consultancy; Genentech, BMS/Celgene, LAM, BioINvent, LOXO, Astra Zeneca, Novartis, M2Gen, Takeda: Research Funding. Kahl: AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding; AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy. OffLabel Disclosure: Venetoclax is not approved for follicular lymphoma or in combination with bendamustine and obinutuzumab

Phase II study of S-1 on alternate days combined with bevacizumab in elderly patients (aged ≥75 years) with metastatic colorectal cancer (mCRC).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 750-750
Author(s):  
Tetsuya Eto ◽  
Toshikazu Moriwaki ◽  
Hiroyasu Ishida ◽  
Shinji Endo ◽  
Yoshiyuki Yamamoto ◽  
...  
Keyword(s):  
Adverse Events ◽  
Elderly Patients ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Group Performance ◽  
Phase Ii Study ◽  
Eastern Cooperative Oncology Group ◽  
Type I ◽  
Grade 3 ◽  
Ecog Ps

750 Background: The alternate-days administration of S-1 was suggested to reduce toxicities such as GI-related adverse events (AEs) or neutropenia maintaining efficacy in some previous reports. This phase II study was aimed to evaluate an alternate-day administration of S-1 combined with bevacizumab in untreated elderly patients with mCRC. Methods: The key eligibility criteria included age ≥75 years, first-line chemotherapy, measurable lesions, Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1, preserved organ function, and refusal of oxaliplatin- or irinotecan-containing regimen as the initial chemotherapy. Patients received 40 mg (body surface area [BSA] ≤1.25 m2), 50 mg (BSA > 1.25 to ≤1.50 m2), or (BSA > 1.50 m2) of S-1 orally, twice a day, on Monday, Wednesday, Friday, and Sunday every week. Bevacizumab of 7.5 mg/kg was administered every 3 weeks. Primary endpoint was progression-free survival (PFS). Expected median PFS was 8.5 months, and efficacy threshold was 5.0 months. The required sample size was calculated as 50 patients, with a 2-sided type I error of 10% and a power of 80%. Results: Of 54 enrolled patients, 50 patients for efficacy and 53 patients for safety were evaluated. The median age was 79 years (range, 75–88), and 56% had an ECOG PS of 0. The median follow-up time was 34.5 months (95% confidence interval [CI], 25.6–44.9). Median PFS was 8.1 months (95%CI, 7.4–10.1). Median overall survival was 22.8 months (95%CI, 16.9–28.5). The response rate and disease control rate were 44% and 88%, respectively. Grade 3 or more hematologic, non-hematologic, and bevacizumab-related AEs were observed in 9%, 11%, and 25% of patients, respectively. The most common grade 3 and 4 treatment-related adverse events were hypertension (11%), nausea (6%), fatigue (6%), anemia (6%), and proteinuria (6%). Treatment-related death caused by cerebral infarction was observed in one patient. Conclusions: The primary endpoint was met. The alternate-days administration of S-1 combined with bevacizumab was well tolerated and effective in elderly patients with mCRC. Clinical trial information: UMIN000010402.

scholarly journals Carfilzomib Thalidomide and Dexamethasone Is Safe and Effective in the Treatment of Relapsed/Refractory Multiple Myeloma: An Open Label Phase II Australasian Leukaemia and Lymphoma Group (ALLG) MM 018/ Asian Myeloma Network (AMN) 002 Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Hang Quach ◽  
Simon J Harrison ◽  
Je-Jung Lee ◽  
Nichloas Murphy ◽  
Jae Hoon Lee ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Board Of Directors ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Research Funding ◽  
Open Label ◽  
Advisory Committees ◽  
Open Label Phase ◽  
Grade 3

Background: The combination of carfilzomib with immunomodulatory drugs (IMiDs) and dexamethasone is active in multiple myeloma (MM). Carfilzomib, thalidomide, and dexamethasone (KTd) has been studied in upfront MM treatment but has not been studied in the setting of relapsed/refractory myeloma (RRMM). The ALLG MM018/ AMN002 is an open-label phase II study of KTd in patients with RRMM. This study was conducted across 16 sites across Australia, New-Zealand, Singapore, South Korea and Taiwan. Method: Patients with RRMM with 1-3 prior lines of treatment were given carfilzomib [K: 20mg/m2 IV cycle 1 days 1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from cycle 1 day 8 onwards], thalidomide (T: 100mg po nocte) and dexamethasone [dex: 40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, T was omitted, and K was given on days 1,2,15,16 and dex days 1,15 every 28-day cycles for a further six cycles. The primary endpoint was PFS. Secondary endpoints were ORR, overall survival, adverse events, and quality of life (QoL). The study had an 80% power to detect a ≥70% PFS at 6.5 months compared to historical ≤50% PFS at 6.5 months expected with Td (Kropff, M. et al. Haematologica 2012), at a significance level of 0.05. Results: This study has completed accrual. Eighty-three patients [median age of 66 years (42-85)] were enrolled with a median follow up of 15.9 (0.9-26) months. ORR rates were 86.4% (≥VGPR 70.2%). Median PFS was 20m (95% CI 15.9-26m). PFS at 6.5 months was 76.2% (95% CI 73.6-84.9%). Median OS has not been reached, and was 75% at 20 months. The most common grade ≥3/4 AEs were peripheral neuropathy (16%), upper respiratory tract infections (12%), dyspnoea (14%), and hypertension (10%). Grade ≥3/4 cardiac AEs occurred in 6%. The median carfilzomib dose that was delivered was 70.7% (32.8-92.6%) of the target dose. Thus far, 41% of patients have completed the intended 18 cycles of treatment. 21% of patients ceased therapy early. The most common reason for early treatment cessation was disease progression (30%) and adverse events (15%). Fifteen patients (18%) have died, 11 were due to MM, two from infection, one from an ischaemic cardiac event, and one from a traffic accident. QoL, as measured by the EQ-5D-5L instrument, remained stable throughout treatment. Conclusion: The ALLG MM018/AMN 002 study has met its primary endpoint. The KTd schedule as outlined in this study is efficacious in patients with RRMM, resulting in a prolonged PFS and a safety profile in line with previous reports for each of carfilzomib and thalidomide. KTd is an active option in jurisdictions where the cost of other IMiDs prohibits regulatory funding. Comparisons of efficacy and adverse events between the Caucasian and Asian populations will be presented at the meeting. Disclosures Quach: Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Haemalogix: Consultancy. Augustson:Roche: Other: Support of parent study and funding of editorial support. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Soo:Hanmi: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

A Phase II Study of Temsirolimus (CCI-779) in Patients with Advanced Leukemias.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4523-4523 ◽  
Author(s):  
Karen W.L. Yee ◽  
Guillermo Garcia-Manero ◽  
Deborah Thomas ◽  
Farhad Ravandi-Kashani ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Disease Progression ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Blast Crisis ◽  
Single Agent ◽  
Mammalian Target Of Rapamycin ◽  
Median Number ◽  
Prior Therapy ◽  
Flat Dose ◽  
Grade 3

Abstract Temsirolimus (CCI-779, Wyeth Pharmaceuticals) has been shown to inhibit proliferation of a variety of tumors and induce G1 cell cycle arrest by preventing activation of the serine/threonine kinase, mTOR (mammalian target of rapamycin), a downstream effector of the PI3K/Akt pathway. Several lines of evidence implicate the PI3K/Akt/mTOR pathway in hematological malignancies. Interim results of a phase II study evaluating the efficacy and toxicity of single-agent temsirolimus in patients with advanced malignancies are presented. Temsirolimus was administered weekly, at a flat dose of 25 mg, as a 30-minute intravenous infusion. Treatment was continued until evidence of disease progression or unacceptable toxicity. To date, 8 patients have been enrolled and 7 are evaluable for efficacy and toxicity (one patient did not receive temsirolimus). Of these 7 patients, 5 had AML, 1 CML-myeloid blast crisis, and 1 ALL. Median age was 68 years (range, 21 to 87 years) and 5 were male. All patients had received prior therapy, median 2 regimens (range, 1 to 3 regimens). The median number of temsirolimus doses administered was 3 (range, 1 to 10) with a median time on study of 18 days (range, 3 to 89+ days). The most common temsirolimus-related adverse events were grade ≤ 2 and consisted of anorexia, nausea and/or vomiting and diarrhea, mucositis, dermatitis, hypertriglyceridemia, hyperglycemia, hypomagnesemia, hypocalcemia, hypokalemia, hypophosphatemia, and fatigue/asthenia. No patient developed nonspecific pneumonitis. Grade 3 toxicities included fatigue/asthenia (2), hyperglycemia (1), painful mucositis with dehydration and electrolyte abnormalities (1), diarrhea with hypokalemia (1), and hypophosphatemia (1). No patient experienced grade 4 toxicities or death from temsirolimus. No patient required dose reductions, but 2 did have dose delays due to grade 3 mucositis (1) and out-of-state hospitalization for pneumonia and atrial fibrillation (1). No patient achieved a complete remission. One patient with heavily pre-treated Philadelphia-negative precursor B-cell ALL had a transient 79% to 91% reduction in peripheral blood blasts 4 days after the first dose of temsirolimus that was maintained for 12 days prior to disease progression with involvement of the synovial fluid in bilateral knees. At the time of analysis, 6 of the 7 patients have discontinued treatment due to disease progression (4), patient refusal (1), or physician decision (1). Preliminary findings indicate that temsirolimus is relatively well-tolerated at a dose of 25 mg per week and may have biologic activity in ALL. Accrual onto the study is currently ongoing.

Phase II Study of the Histone Deacetylase Inhibitor Panabinostat (LBH589) in Patients with Low or Intermediate-1 Risk Myelodysplastic syndrome

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1731-1731
Author(s):  
Sophie Dimicoli ◽  
Elias Jabbour ◽  
Gautam Borthakur ◽  
Tapan Kadia ◽  
Zeev Estrov ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Median Duration ◽  
Lower Risk ◽  
Response Rate ◽  
Phase Ii Study ◽  
Single Agent ◽  
Clinical Activity ◽  
Number Of Patients ◽  
Deacetylase Inhibitor

Abstract Abstract 1731 Panabinostat is a very potent panhistone deacetylase inhibitor (HDACi) with activity in acute myelogenous leukemia (CCR 2006;12: 4628). We hypothesized that single agent panabinostat could be active in patients with low and intermediate-1 risk MDS. Oral route of administration and safety profile further increased interest in this approach. To test this concept we designed a phase II study of panabinostat for patients above 18 years of age with lower risk disease. Patients could have received prior therapy or be treatment naïve. Appropriate renal, hepatic and cardiac functions were required. Patients were excluded if they had previous HDACi treatment. Patients with history of cardiac pathology such as rhythm alterations were excluded from the study. Use of drugs that could induce QT prolongation and CYP3A4 inhibitors were not allowed. Panabinostat was used at dose of 20 mg orally three times a week for consecutive 3 weeks with cycles repeated every 4 weeks. The primary objective of the study was overall response rate defined by IWG. A maximum of 40 patients could be enrolled. The study was to stop early if the expected response rate was less than 15%. Stopping rules were as follows: Stop if the number of patients with hematologic improvement/the number of patients evaluated was 0/15 or 1/32. The study also contained a stopping rule for non-hematological toxicity. Thirteen patients were enrolled between August 2009 and December 2010. Median age was 70 years (range 47 to 84, 84% of patients older than 60), 70% were transfusion dependent, 70% had intermediate-1 risk MDS, most patients were diploid but one patient with del(5q), one with trisomy 8, one with complex cytogenetics and 2 with deletion of 20q were included. Median percent of marrow blasts was 1% (range 1 to 6%). At start of therapy, median hemoglobin was 9.5 (range 7.5–11.2 G/dL), median platelet count was 56 (range 6–431 k/uL) and median white blood cell count was 4.6 (range 0.8–20.3 k/uL). Approximately 40% had previous therapy for MDS including hypomethylating agents, lenalidomide and investigational agent. Median number of prior therapies for treated patients was 2 (range 1 to 4). Median duration of disease at time of enrollment was 10 months (range 1–50). Patients received a median of 4 cycles of panabinostat (range 1–9). Of 13 patients, 1(8%) achieved a hematological improvement including both an erythroid and platelet response that lasted for 3 months. No complete remissions or partial responses were documented. Six patients (46%) had stable disease for a median duration of 6 months (range 2–13.6). Median overall survival was 15 months (1–31 months). Two patients died because progression to AML. Therapy was well tolerated: no major adverse events were documented except for one patient that developed significant QTc prolongation. Adverse events included mild fatigue and gastrointestinal toxicity. As a biomarker of molecular activity, histone H3 acetylation was measured in 5 patients with variable results. Induction of acetylation was documented in 2. Despite the fact that the stopping rule for activity was not officially met, because of the very modest clinical activity observed, the study was closed to new patient entry. In conclusion, panabinostat given as a single agent orally at a dose of 20 mg thee times a week for 3 weeks followed by one week of rest has limited clinical activity in patients with lower risk MDS. Disclosures: No relevant conflicts of interest to declare.

A Phase II Multicenter Study of the Histone Deacetylase Inhibitor (HDACi) Abexinostat (PCI-24781) in Relapsed/Refractory Follicular Lymphoma (FL) and Mantle Cell Lymphoma (MCL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 55-55 ◽  
Author(s):  
Andrew M. Evens ◽  
Julie M Vose ◽  
Wael Harb ◽  
Leo I. Gordon ◽  
Robert Langdon ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Safety Profile ◽  
Tumor Size ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Employment Equity ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 55 Background: Abexinostat (PCI-24781) is a novel oral pan-HDACi that has previously demonstrated potent preclinical activity in lymphoma cell lines and animal models (Evens et al, Clin Ca Res 2009) as well as a tolerable safety profile in phase I solid tumor clinical studies (Undevia et al, ASCO 2008). In a phase I single-agent clinical trial in patients (pts) with multiply relapsed/refractory lymphoma and leukemia, anti-tumor activity was noted in FL and MCL; 4/4 FL pts showed durable clinical benefit with median time on treatment of >8 months; 1 of 2 MCL pts had a complete remission (CR) and remains on treatment for >3 years. Based on these encouraging single-agent abexinostat data, a phase II extension study was completed in relapsed/refractory FL and MCL. Methods: The primary objective of this phase II study was objective response rate (ORR, complete [CR] and partial remission [PR]), while reduction in tumor size (CR + PR + stable disease) and safety were also examined. Abexinostat was given orally twice daily at 45mg/m2 on a 4-week cycle for 7 days/week every other week, which is the previously established dose and schedule identified in the phase I study. For pharmacodynamic correlative analyses, tubulin and histone acetylation were measured in peripheral blood mononuclear cells (PBMCs) at pre-dose and 4 hours after the first dose of abexinostat. Results: A total of 30 pts were enrolled (n=16 FL and n=14 MCL pts) of which 25 were response-evaluable. The median age was 67 years (36–81) and the median prior therapies were 3 (1–5), 77% of which were rituximab-containing and one-third (33%) had undergone prior autologous stem cell transplant (31% FL, 36% MCL). The ORR in all pts was 48% (12/25). A reduction in tumor size was observed in 86% (12/14) of FL pts, while the ORR in FL was 64% (9/14); the FL intent-to-treat ORR was 56%. With a median follow-up of 10.3 months (1.2–20.9), the progression-free probability was 86% in FL pts. Furthermore, the median duration of response (DOR) in FL pts has not been reached, as 5 responders remain on study. Notably, 4 FL pts were on treatment for over 16 months. Among MCL pts, reduction in tumor size was noted in 27% (3/11), while the ORR was similar at 27% (3/11). The median progression-free survival (PFS) in MCL pts was 4 months (1–12), while the DOR in the 3 responding patients were 2+, 3, and 6+ months. Therapy was overall well tolerated. The most common treatment-related adverse events (AEs) of any grade (> 20% incidence) include: nausea (60%), fatigue (57%), diarrhea (50%), thrombocytopenia (37%), vomiting (30%), anemia (27%), decreased appetite (23%), dysgeusia (20%) and neutropenia (20%). The most common grade 3/4 related AEs (> 5% incidence) were thrombocytopenia (17%), neutropenia (13%), fatigue (13%), and anemia (7%). There were no deaths reported on the study. Pharmacodynamic analyses revealed that a majority of pts had increased tubulin acetylation in PBMCs, however this finding did not correlate with response or toxicity. Conclusion: In this phase II study, the novel pan-HDACi, abexinostat, was clinically active and overall well tolerated in relapsed/refractory B-cell lymphoma. The safety profile was consistent with this class of agents with <20% of subjects experiencing grade 3/4 cytopenias (during the course of prolonged treatments). Moreover, there was significant clinical activity noted in FL with an ORR of 64%, which included several durable responses in this multiply-relapsed pt population. Further examination of single-agent abexinostat in FL is warranted. Disclosures: Off Label Use: PCI24781 is not FDA approved; it is an investigational agent. Plasencia:Pharmacyclics: Employment, Equity Ownership. Sirisawad:Pharmacyclics: Employment, Equity Ownership. Yue:Pharmacyclics: Employment, Equity Ownership. Luan:Pharmacyclics: Employment, Equity Ownership. Siek:Pharmacyclics: Employment, Equity Ownership. Zhou:Pharmacyclics: Consultancy. Balasubramanian:Pharmacyclics: Employment, Equity Ownership.

Multi-institutional phase II study of carboplatin-gemcitabine combination chemotherapy in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18179-18179
Author(s):  
J. Sasaki ◽  
H. Uramoto ◽  
K. Kashiwabara ◽  
H. Kishi ◽  
E. Moriyam ◽  
...  
Keyword(s):  
Phase Ii ◽  
Combination Chemotherapy ◽  
Advanced Nsclc ◽  
Response Rate ◽  
Group Performance ◽  
Phase Ii Study ◽  
Single Agent ◽  
Objective Response ◽  
Efficacy And Safety ◽  
Grade 3

18179 Background: Because elderly pts may tolerate platinum-based combination chemotherapy poorly, single-agent chemotherapy is selected for the treatment regimen. However, retrospective subgroup analyses have consistently indicated that elderly pts indeed benefit from platinum-based combination chemotherapy as well as their younger counterparts. This phase II study evaluated the efficacy and safety of carboplatin-gemcitabine combination chemotherapy in elderly pts with advanced NSCLC. Methods: Fifty-four pts aged more than 70 years old (median, 77; range, 70–88) with previously untreated advanced NSCLC were enrolled on this trial. Additional criteria included the presence of measurable lesions, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. Pts received carboplatin at an area under the curve of 4 mg/ml/min on the first day and gemcitabine at 1000 mg/m2 on the first and eighth day of consecutive 3 week periods. The primary endpoint was to determine the objective response rate of this platinum-doublet regimen. The RECIST criteria were used to measure response. Results: Enrolled pts included 15/39 with stage IIIB/IV diseases. Fifty-one out of enrolled pts were eligible for efficacy and safety analyses. The median number of treatment cycles was 4 (range, 1–7). Fifteen partial responses (response rate: 29%) were obtained. The median TTP was 118 days. Hematological toxicities of grade 3/4 included leukopenia (46%), neutropenia (72%) and thrombocytopenia (50%). Non-hematological toxicities of grade 3/4 included nausea (6%), appetite loss (7%), fatigue (7%) and infection (9%). Conclusions: The combination carboplatin-gemcitabine at these doses has shown activity with a favorable toxicity profile for fit elderly pts with advanced NSCLC. No significant financial relationships to disclose.

Phase II study for the suboptimally debulked advanced ovarian cancer: Intravenous platinum followed by interval debulking surgery and intravenous paclitaxel + intraperitoneal cisplatin (KCOG9812 study)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5576-5576
Author(s):  
H. Tsubamoto ◽  
K. Ito ◽  
Y. Itani ◽  
K. Ito ◽  
T. Iijima ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Stage Iiib ◽  
Hematologic Toxicity ◽  
Treatment Schedule ◽  
Debulking Surgery ◽  
Interval Debulking Surgery ◽  
Grade 3

5576 Background: Intraperitoneral administration (IP) of cisplatin is recommended by National Cancer Institute for the patients with optimally debulked epitherial ovarian cancer (EOC). However, the advantage is not determined for the suboptimally debulked EOC after the initial surgery. We conducted a phase II study of cisplatin IP after the interval debulking surgery (IDS) following 3 cycles of intravenous platinum. Methods: The initial planned sample size was 30. Eligible patients had previously untreated, histologically confirmed EOC or primary peritoneal carcinoma (PPC) of FIGO stage IIIB-IV with suboptimal (> 1 cm) residual disease. Carboplatin AUC 4 iv d1 and cisplatin 50 mg/sqm iv d3 q21d for 3 cycles. After IDS, paclitaxel 175 mg/sqm iv d1 (or paclitaxel 60 mg/sqm iv d1,d8,d15) and cisplatin 75mg/m2 IP q21d for 4 cycles. Primary endpoint was progression-free survival (PFS) and secondary endpoints were overall survival (OS) and toxicity. Results: 33 patients were enrolled since 1998 till 2005. The median age was 55 (range 19–77). ECOG PS 0/1/2 = 33%/36%/31%; stage IIIB/IIIC/IV = 6%/64%/30%; 91% serous papillary histology. Optimal interval debulking surgery was possible in 85%: none (61%), < 1 cm (24%). Grade 3 or 4 (CTCAE ver.3) non-hematologic toxicity was seen in one patient of neurotoxicity. Grade 3 or 4 hematologic toxicities include: neutropenia (37%), infection (4%), thrombocytopenia (11%). 55% were completed the treatment schedule. The reasons for discontinuing were drug resistance (12%), subileus (4%), elevation of serum creatinine (12%), G3 neurotoxicity (4%), IP catheter block (12%) and infection (4%). Primary recurrent sites of total 20 patients before the second line chemotherapy or surgery were peritoneal cavity (30%), distant metastasis (45%), retroperitoneal lymph nodes (15%), and elevation of serum CA125 (10%). Median PFS was 24 months; median overall survival was 48 months; median follow-up was 36 months (range 15–100). Conclusions: This treatment including cisplatin IP after IDS for the patients with the initially suboptimally debulked EOC was feasible, and showed good prognosis with the small number of the intraperitoneal recurrence. [Table: see text]

A phase II study of GW786034 (pazopanib) in patients with recurrent or metastatic invasive breast carcinoma: Results after completion of stage I: A trial of the Princess Margaret Hospital Phase II Consortium

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1133-1133 ◽  
Author(s):  
S. K. Taylor ◽  
S. Chia ◽  
S. Dent ◽  
M. Clemons ◽  
P. Grenci ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adverse Events ◽  
Phase Ii ◽  
Progressive Disease ◽  
Single Agent ◽  
Objective Response ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Lesion Size ◽  
Grade 3

1133 Background: Pazopanib, an oral small molecule inhibitor of VEGFR, PDGFR, and KIT, has demonstrated activity in phase I, with a recommended phase II dose of 800 mg/d (Hurwitz H et al, J Clin Oncol. 2005;23[16 suppl]:3012.1). We evaluated the activity of single agent pazopanib in recurrent or metastatic breast cancer (MBC). Methods: In this 2-stage design, patients with recurrent or MBC received pazopanib 800 mg/d. The primary endpoint was objective response rate (ORR) of 20%. Response in 3 out of 18 patients was required to go to stage 2. Treatment was continued until progression. Results: 21 patients entered stage 1; 67% were ER positive and all were HER-2-negative. Prior lines of chemotherapy were 1 in 76% and 2 in 14%. Of the 19 evaluable patients, 2 patients remain on treatment. 14 (74%) stopped due to progressive disease, 2 (10%) due to adverse events, and 1 (5%) due to patient request. Best response was partial response (PR) in 1 (5%), stable disease (SD) in 11 (58%), and progressive disease in 7 (37%). Clinical benefit rate (CR, PR, or SD for ≥ 6 months) was 26%. Median time to progression (TTP) was 3.7 months (95% C.I. 1.7 months - not reached). 9 out of 18 patients (50%) with measurable target lesions had some decrease in target lesion size. Estimated progression-free survival at 3 months was 55%, and 28% at 6 months. Adverse events were grade 3/4 elevations in AST (14%) and ALT (10%), and grade 3 hypertension and neutropenia (14% each). Other common events were grade 1/2 lymphopenia, neutropenia, diarrhea, fatigue, skin hypopigmentation, hypertension, nausea, vomiting, anorexia, and headache. Conclusions: Pazopanib is well tolerated and demonstrates activity in pretreated breast cancer. While the target ORR of 20% has not been met, rates of SD and TTP are comparable to other active agents in this setting, and therefore pazopanib may be an interesting agent for future studies in breast cancer. [Table: see text]

Sign in / Sign up

Export Citation Format

Share Document