A Multi-Center, Open-Label Study To Evaluate the Safety and Efficacy of Pentostatin, Cytoxan, and Rituxan (PCR) in the Treatment of Previously Untreated or Treated, Stage II, III or IV Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1356-1356
Author(s):  
Raul R. Mena ◽  
Mehdi M. Moezi ◽  
Robert L. Robles ◽  
Maureen Cooper
Keyword(s):  
Febrile Neutropenia ◽  
Single Agent ◽  
Previous Treatment ◽  
The Elderly ◽  
Lymphocytic Leukemia ◽  
Stage Ii ◽  
Hematologic Toxicity ◽  
Open Label ◽  
Previously Treated ◽  
Grade 3

Most treatment regimens for CLL are fludarabine-based regimen, which is highly myelosuppressive and immunosuppressive that frequently results in severe infections, especially among the elderly. Combination therapy with pentostatin (P), a purine analog, cyclophosphamide (C), a DNA alkylator, and rituximab (R), an anti-CD20 monoclonal antibody, based on the single-agent activities, documented synergy, and non-overlapping toxicity profiles, may represent a promising approach in the treatment of these patients. To further investigate the efficacy of the PCR regimen for the treatment of CLL, we conducted a phase II study. Patients diagnosed of stage II, III or IV CLL (modified Rai classification), previously untreated or treated, were eligible. All patients were treated with intravenous infusions of P (4 mg/m2), C (600 mg/m2), and R (375 mg/m2) on day 1 of a 21-day cycle for at least 8 cycles. 2 additional cycles were given for patients with PR or SD after cycle 8 or patients with CR/CRu first evident at cycle 8. Clinical evaluation was performed after cycles 2, 4, 6, 8, and 10 if necessary. Dose modification for hematologic toxicity may be increased to the previous higher level when a hematologic toxicity returned to normal. Two 25% dose reductions or one 50% dose reduction were allowed for nonhematologic toxicity. Eighty-five patients with CLL, 61 previously untreated, 13 previously treated, and 11 with unknown treatment history were enrolled in the study. The median age was 64 years (range 35–83) and 66.7% were ECOG PS 0, 29.6% PS1, 3.7% PS 2. A total of 446 cycles were given, with a median of 6 cycles per patient. 69 patients received at least two cycles of treatment and were evaluated for response.16 patients were not evaluated for response due to deaths (n=3), withdrawal of consent (n=3), unacceptable toxicities (n=3), treatment delay (n=2), screening failure (n=1), missing data (n=3), administrative reason (n=1). The highest achieved response rate (RR) was 56.5%, with 11 (12.9%) CR, 8 (9.4%) CRu, 29 (34%) PR, 20 (23.5%) SD, 1 (1.1%) progressed. Stratified according to previous treatment status, patients with previously untreated CLL had an RR of 42.4% (CR, CRu 17.7%) while that of the previously treated was 4.7% (CR 1.2%). 11 (13.0%) patients discontinued treatment due to toxicities. Grade 3/ 4 hematological adverse events documented included 9 grade 4 neutropenia, 16 grade 3 neutropenia, 4 grade 3 anemia, 2 grade 4 anemia, and 5 grade 3 thrombocytopenia. Infectious complications were observed in 8 patients including 5 grade 3 febrile neutropenia, 1 grade 4 febrile neutropenia, and 1 grade 3 and 1 grade 4 infection. A total of 8 deaths, of which 6 were in elderly patients (>70 years old) were recorded, including 1 acute respiratory failure, 1 cholangiocarcinoma, 1 pulmonary edema, 2 sepsis, and 3 unknown causes. The PCR regimen is active patients with stage II, III, and IV CLL. The study is currently on-going and updated results will be presented.

A Multi-Center, Open-Label Study To Evaluate the Safety and Efficacy of Pentostatin, Cytoxan, and Rituxan (PCR) in the Treatment of Previously Untreated or Treated, Stage III or IV, Low-Grade B-Cell Non-Hodgkin’s Lymphoma (NHL) or Bulky Stage II Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1354-1354
Author(s):  
Raul R. Mena ◽  
Neil P. Christiansen ◽  
Yudhishtra Markan ◽  
Lalita Pandit
Keyword(s):  
Febrile Neutropenia ◽  
B Cell ◽  
Single Agent ◽  
Stage Ii ◽  
Stage Iii ◽  
Hematologic Toxicity ◽  
Low Grade ◽  
Purine Analog ◽  
Previously Treated ◽  
Grade 3

Abstract The decision to treat indolent B-cell NHL is often based on progression of the disease. Most regimens have utilized fludarabine as the purine analog but the myelosuppression and immunosuppression of fludarabine combinations frequently results in severe infections. Combination therapy with pentostatin (P), a purine analog, cyclophosphamide (C), a DNA alkylator, and rituximab (R), an anti-CD20 monoclonal antibody, based on the single-agent activities, documented synergy, and non-overlapping toxicity profiles, may represent a promising approach in the treatment of these patients. To further investigate the efficacy of the PCR regimen for the treatment of indolent NHL, we conducted a phase II study. Patients diagnosed of bulky stage II, stage III/IV low-grade NHL (REAL classification), previously untreated or treated, were eligible. All patients were treated with intravenous infusions of P (4 mg/m2), C (600 mg/m2), and R (375 mg/m2) on day 1 of a 21-day cycle for at least 8 cycles. 2 additional cycles were given for patients with PR or SD after cycle 8 or patients with CR/CRu first evident at cycle 8. Clinical evaluation was performed after cycles 2, 4, 6, 8, and 10 if necessary. Dose modification for hematologic toxicity may be increased to the previous higher level when a hematologic toxicity returned to normal. Two 25% dose reductions or one 50% dose reduction were allowed for nonhematologic toxicity. One hundred patients with indolent NHL, 68 previously untreated, 26 previously treated, and 6 with unknown treatment history, were enrolled in the study. The median age was 61 years (range 29–84) and 63.4% were ECOG PS 0, 36.6% PS1. A total of 550 cycles were given, with a median of 6 cycles per patient. 8 patients were not evaluated for response due to withdrawal of consent (n=1), unacceptable toxicities (n=3), and missing data (n=4). 92 patients received at least two cycles of treatment and were evaluated for response. The highest response rate (RR) achieved was 68%, with 10 (10%) CR, 12 (12%) CRu, 46 (46%) PR, 23 (23%) SD, and 1 (1%) disease progression. Stratified according to previous treatment status, patients with previously untreated NHL had an RR of 47% (CR, CRu 17%) while that of the previously treated was 17% (CR 7%). 14 (14.0%) patients discontinued treatment due to toxicities. Grade 3/ 4 hematological adverse events documented included 10 grade 4 and 16 grade 3 neutropenia. Infectious complications were noted in 8 patients including 3 grade 3 febrile neutropenia, 2 grade 4 febrile neutropenia, and 3 grade 3 infections. A total of 4 deaths were recorded, including 1 due to acute myocardial infarction, 1 suspected cardiac event and 2 unknown causes. This immunochemotherapeutic regimen is active in patients with indolent NHL. The study is currently on-going and updated results will be presented.

Oxaliplatin Plus Irinotecan Compared With Irinotecan Alone as Second-Line Treatment After Single-Agent Fluoropyrimidine Therapy for Metastatic Colorectal Carcinoma

2008 ◽  
Vol 26 (28) ◽  
pp. 4544-4550 ◽  
Author(s):  
Daniel G. Haller ◽  
Mace L. Rothenberg ◽  
Alfred O. Wong ◽  
Piotr M. Koralewski ◽  
Wilson H. Miller ◽  
...  
Keyword(s):  
Median Overall Survival ◽  
Single Agent ◽  
Phase Iii ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Open Label ◽  
Sensory Disturbances ◽  
Previously Treated ◽  
Grade 3

Purpose To determine whether irinotecan plus oxaliplatin (IROX) is superior to irinotecan alone in patients with metastatic colorectal cancer (CRC) previously treated with single-agent fluoropyrimidines. Patients and Methods A phase III, randomized, open-label, multicenter study of patients with metastatic or recurrent CRC that had progressed or recurred during or after adjuvant or first-line fluoropyrimidines (fluorouracil/leucovorin or capecitabine, the latter only for metastatic CRC). Patients received IROX (irinotecan 200 mg/m2 plus oxaliplatin 85 mg/m2) or irinotecan alone (350 mg/m2) every 3 weeks. Results At the data cutoff (when 447 of 628 randomly assigned patients had died), median overall survival was 13.4 months (95% CI, 12.4 to 14.7 months) and 11.1 month (95% CI, 10.0 to 12.7 months) in the IROX and irinotecan groups, respectively (hazard ratio = 0.78; 95% CI, 0.65 to 0.94; P = .0072). Overall response rate (22% v 7%, respectively; P < .0001), median time to progression (5.3 v 2.8 months, respectively; P < .0001), and improvement in tumor-related symptoms (32% v 19%, respectively; P = .0072) were also improved with IROX as compared with irinotecan. With the exception of granulocytopenia (25% v 13%), diarrhea (28% v 23%), and sensory disturbances (5% v 0%), grade 3 to 4 toxicities were comparable between the IROX and irinotecan groups, respectively. Conclusion IROX is an effective treatment for metastatic CRC that has progressed after first-line fluoropyrimidine therapy. IROX improves efficacy compared with irinotecan alone, providing an additional option in the postadjuvant or second-line treatment setting for patients who experience treatment failure with single-agent fluoropyrimidine therapy.

A Pilot Study of Genasense® (Oblimersen Sodium, Bcl-2 Antisense Oligonucleotide), Fludarabine and Rituximab in Previously Treated and Untreated Subjects with Chronic Lymphocytic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4827-4827 ◽  
Author(s):  
Asher Alban Chanan-Khan ◽  
Blanche Mavromatis ◽  
Kanti R. Rai ◽  
Philomena Casey ◽  
Steven Novick ◽  
...  
Keyword(s):  
Adverse Events ◽  
Lymphocyte Count ◽  
Alkylating Agents ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Lymphocytic Leukemia ◽  
Serious Adverse Events ◽  
Reduced Dose ◽  
Previously Treated ◽  
Grade 3

Abstract Bcl-2 is an anti-apoptotic protein closely linked to chemotherapy resistance and inferior survival in patients (pts) with CLL. Genasense(GNS) enhances apoptosis induced by fludarabine (F), dexamethasone, and rituximab (R) in vitro, and has limited single-agent activity in heavily pre-treated CLL pts. Down-regulation of Bcl-2 may further sensitize CLL cells to apoptosis induced by F and R without exposing subjects to the toxicity of alkylating agents. CLL and NHL pts occasionally exhibit a “cytokine release syndrome” (spiking fever, back pain, and occasional hypotension) with GNS treatment. We hypothesized that a “step dosing” approach with GNS, similar to that sometimes used for R, could ameliorate these effects and allow safe and effective combination of this agent with F and R. We are currently evaluating this combination in pts with either previously untreated (UT) or relapsed, previously treated (PT) CLL who require systemic treatment. Eligibility includes: plts ≥ 50,000/mm3; serum Cr ≤ 1.5 mg/dL; adequate organ function; negative Coombs; no history of autoimmune hemolytic anemia. In cycle 1, GNS is given by continuous intravenous infusion at 1.5 mg/kg/d days 1 to 7. R is given on a dose-escalating schema (day 4, 125 mg/m2; day 6, 250 mg/m2). F (25 mg/m2/d) is given on days 6 to 8. In subsequent 28-day cycles (up to 6), the dose of GNS is escalated to 3 mg/kg/d days 1 to7 days, with R 375 mg/m2 on day 5 and F days 5 to7. To date, 20 pts have been enrolled (17 PT and 3 UT). Characteristics included: median age, 62 yrs (range 39 to 82 yrs); Rai stage III (2 pts) and IV (6 pts). Prior to administration of either F or R, single-agent GNS treatment at the initial reduced dose in Cycle 1 resulted in a median decrease in lymphocytes of 15% (among all patients regardless of decline in lymphocyte count) (Baseline: 48.3 cells x 103/ml; day 4: 40.1 cells x 103/ml). For the 13 pts who experienced a decline in lymphocyte count in cycle 1 prior to F and R, the median percentage change was 17%, with 4 pts having a &gt; 25% decrease. Three PT pts discontinued from study treatment prior to completing 6 cycles, 2 due to disease progression, and 1 with Grade 3 thrombocytopenia that was unresolved after 4 weeks. Among the 20 pts treated to date (9 ongoing), the most common grade 3 or higher adverse events have been neutropenia, pyrexia and thrombocytopenia. Serious adverse events have been noted in only 6 of 20 pts (all PT pts) and have included 2 pts with fever (1 neutropenic), 2 R infusion reactions, 1 lymph node abscess and 1 tumor lysis syndrome (with sepsis). Conclusions: 20 pts have been treated with combination GNS, F and R. Single-agent activity with GNS has been observed at a reduced dose of 1.5 mg/kg/d in cycle 1. The “step dosing” approach appears to be a well-tolerated, alternative approach to the administration of GNS. Further details of safety and efficacy will be presented.

Tolerability and Efficacy of Bortezomib Added to CVP-R for Previously Untreated Advanced Stage Follicular Lymphoma: Interim Analysis of a Phase II Study by the NCIC Clinical Trials Group.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1576-1576 ◽  
Author(s):  
Laurie H Sehn ◽  
David A Macdonald ◽  
Sheldon H. Rubin ◽  
Morel Rubinger ◽  
Kevin R Imrie ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Phase Ii ◽  
Interim Analysis ◽  
Standard Dose ◽  
Single Agent ◽  
Acceptable Level ◽  
Phase Iii ◽  
Hematologic Toxicity ◽  
Open Label ◽  
Grade 3

Abstract Background: Despite recent improvements in therapy, follicular lymphoma (FL) remains incurable with standard treatment, warranting investigation of new approaches. Bortezomib, the first-in-class proteasome inhibitor has demonstrated promising efficacy as a single agent in heavily pretreated patients (pts) with FL. This is the first study to evaluate the safety and efficacy of the addition of bortezomib to cyclophosphamide, vincristine, prednisone and rituximab (CVP-R). Methods: This is a phase II multi-center open-label trial adding bortezomib (1.3 mg/m2 day 1&8) to standard dose C(750 mg/m2) V(1.4 mg/m2, capped at 2 mg) P(40 mg/m2 × 5) –R(375 mg/m2) for up to 8 cycles in pts with newly diagnosed stage III/IV FL requiring therapy. Planned accrual is 90 patients. A two-stage design was employed with a planned interim analysis of the first 28 patients to ensure an acceptable level of neurotoxicity (defined as less than 5/28 patients with grade 3/4 neurotoxicity after the first 4 cycles) and meaningful response rate (more than 12/28 patients with a complete response following 8 cycles), prior to enrolling remaining patients. Results: Median age of the first 28 patients was 55 years (range, 30–73). Fifty percent were male and 79% had stage IV disease. FLIPI score at study entry: low 14%, intermediate 43%, high 43%. Overall, the combination of bortezomib and CVP-R was extremely well tolerated. To date, no pts have developed grade 4 neurotoxicity and only 1/28 (4%) has developed grade 3 neurotoxicity within the first 4 cycles (neuropathic pain which resolved without need for treatment modification). The incidence of grade 1 and 2 neurotoxicity was 54% and 25% respectively. Only 3 pts discontinued therapy prematurely (2 pt refusal, 1 progressive disease). Ninety-four percent of planned bortezomib treatments in the first four cycles and 93% of vincristine doses were administered without dose reduction. Hematologic toxicity was mild, with no pts experiencing grade 3/4 anemia or thrombocytopenia. Only 2 episodes of febrile neutropenia occurred and no grade 3/4 infections were noted. Although it is too early to report on efficacy in this ongoing trial, response objectives for stage I have been met, and enrollment to stage 2 is underway. Conclusions: The addition of bortezomib to standard dose CVP-R is very well tolerated, with an acceptable level of neurotoxicity, without compromising the delivery of bortezomib or vincristine. This ongoing study will provide toxicity and efficacy data to facilitate the development of a planned phase III trial.

Frontline Combined Chemoimmunotherapy with Fludarabine, Cyclophosphamide, Alemtuzumab and Rituximab (CFAR) in High-Risk Chronic Lymphocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 208-208 ◽  
Author(s):  
Sameer A Parikh ◽  
Michael Keating ◽  
Susan O'Brien ◽  
Alessandra Ferrajoli ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Hematologic Toxicity ◽  
Frontline Therapy ◽  
Grade 3 ◽  
Tract Infections ◽  
Cmv Reactivation

Abstract Abstract 208 Background: Combined chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has excellent clinical activity as frontline therapy for patients (pts) with chronic lymphocytic leukemia (CLL). In a subset of pts who exhibited high-risk features, such as serum beta-2 microglobulin (B2M) ≥4 mg/L; the complete remission (CR) was lower and time to progression (TTP) and overall survival (OS) were shorter; therefore characterizing these pts as high-risk. Alemtuzumab (A) has activity as a single-agent and in combination with F in pts with relapsed/refractory CLL. To improve the CR and OS for pts with high-risk CLL, we added A to the FCR regimen (CFAR) as frontline therapy in a Phase II clinical trial. Methods: All pts who met NCI-WG criteria to initiate therapy, were < 70 years and had a B2M ≥4 mg/L were eligible for the study. Frontline CFAR consisted of C-200 mg/m2 D3-5, F-20mg/m2 D3-5, A-30mg IV D1,3,5, and R-375–500 mg/m2 D2. Courses were repeated every 28 days for a total of 6 courses. All pts received pegylated filgrastim 6mg SC with each course of therapy. All pts received allopurinol for tumor lysis prophylaxis. Antibiotic prophylaxis with TMP/SMX DS and valacyclovir or valganciclovir was also given to all pts. CMV antigenemia was monitored before each course. Results: A total of 60 pts were enrolled from July 2005 through August 2008 (Table). One pt was lost to follow-up. The median age was 59 yrs (range 42–69) and 44 (75%) were male. Median B2M was 5.1 mg/L (4–11.6); HGB was 11.5gm/dL (5.5–15.1); PLT was 139 k/μL(41–446); WBC was 100k/μL (5–665); ALC was 92k/μL (4–619); and 30 pts (51%) were Rai stage III-IV. The median number of courses administered was 4 (2–6); reasons for not completing 6 courses included delayed recovery of counts (18), infection (8), AIHA (4), treatment failure (3) and pt. choice (2). CR was achieved in 70%, nPR in 3%, PR in 18%, and 7% pts did not respond, leading to an ORR of 92% (Table). There was no significant correlation between CR or OR with Rai Stage, IgVH mutation status, FISH status, ZAP70 and CD38 expression. After a median follow-up of 24 months (3–49), 19(32%) pts have progressive disease. Patients with 17p deletion and unmutated IgVH had significantly shorter TTP as shown in the >Table. Eleven (19%) pts have died: 4 with disease progression after achieving CR; 2 who did not respond; 2 with Richter's transformation; 1 transformed into AML; 1 due to metastatic lung cancer; and 1 due to severe pneumonia 8 months after achieving CR. Grade 3/4 neutropenia and thrombocytopenia occurred in 31% and 13% courses. Major infections, including pneumonia and sepsis, were reported for 10(17%) pts. Minor infectious such as bronchitis, urinary tract infections and herpes zoster were reported for 15(25%) pts. In a historic cohort of high-risk pts treated with FCR, grade 3/4 neutropenia and thrombocytopenia occurred in 31% and 10% courses; and major and minor infections were seen in 15% and 23% pts respectively, all comparable to that seen with frontline CFAR. A-associated infusion reactions occurred in 42 (71%) pts. CMV reactivation occurred in 7 (12%) pts, all of whom were on valacyclovir prophylaxis. There was 1 death due to CMV pneumonia; all other episodes of CMV reactivation were promptly treated with valaganciclovir leading to resolution of fever and/or antigenemia. The median OS for all pts has not been reached (49+mo) and the median TTP is 38 months. Conclusion: CFAR is an active frontline regimen in high-risk pts with CLL. Although CR rates in pts with other high-risk features such as 17p deletion and unmutated IgVH were >50%, TTP was significantly shorter for these pts than for pts without these features. With current follow-up, OS, TTP, infectious complications and grade 3/4 hematologic toxicity are comparable to historic high-risk pts treated with FCR. Disclosures: Keating: Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wierda:Genentech: Consultancy, Honoraria; Genzyme: Research Funding.

Comparison of two doses of cabazitaxel plus prednisone in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) previously treated with a docetaxel (D)-containing regimen.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4692-TPS4692 ◽  
Author(s):  
Mario A. Eisenberger ◽  
Anne-Claire Hardy-Bessard ◽  
Loic Mourey ◽  
Paul N. Mainwaring ◽  
Daniel Ford ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Hematologic Toxicity ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Measurable Disease ◽  
Previously Treated ◽  
Grade 3 ◽  
Ecog Ps

TPS4692^ Background: The phase III TROPIC study (NCT00417079) reported a significant improvement in overall survival (OS) for cabazitaxel (Cbz) + prednisone (P;CbzP) (25 mg/m2 IV Q3W/10 mg PO QD) vs mitoxantrone (M) + P (MP) (median OS 15.1 vs 12.7 mos; HR 0.70; P < 0.0001) in pts with mCRPC (also known as hormone-refractory prostate cancer) previously treated with a D-containing regimen. CbzP is approved by the FDA, EMA and other health authorities for the treatment of pts with mCRPC that has progressed after a D-containing regimen. Cbz toxicity is consistent with other taxanes; compared with M, more hematologic toxicities are reported (primarily Grade 3–4 neutropenia). Phase I/II studies identified 20 and 25 mg/m2 as recommended doses; 25 mg/m2 was selected for the phase III TROPIC study. As pooled data show Grade 3–4 neutropenia incidence is lower with Cbz < 25 mg/m2 (61%) vs ≥ 25 mg/m2 (74%), it is of interest to assess if reducing the Cbz approved dose in mCRPC lessens hematologic toxicity and is non-inferior in terms of efficacy. Methods: PROSELICA (NCT01308580) is a randomized, open-label, multinational, phase III study comparing 20 mg/m2 and 25 mg/m2 Cbz for efficacy and tolerability. Pts with a life expectancy > 6 mos, ECOG PS ≤ 2, histologically/cytologically confirmed metastatic prostate adenocarcinoma resistant to hormone therapy and previously treated with a D-containing regimen are eligible. Pts are randomized 1:1 to receive Cbz 20 mg/m² or 25 mg/m² IV Q3W + P 10 mg PO QD, treated until disease progression, unacceptable toxicity or withdrawal of consent (max 10 cycles), and stratified according to ECOG PS, measurable disease (yes/no) and region. The primary endpoint is OS (non-inferiority design). Secondary endpoints include safety, progression-free survival (PCWG2 criteria), PSA and pain progression and response, tumor response in pts with measurable disease and health-related quality of life. Cbz PK and pharmacogenomics will be assessed in pt subgroups. Planned enrollment is 1,200 pts. Study start was in May 2011; as of Jan 2012, 270 pts had been enrolled. The first DMC meeting recommended continuing the study without change.

Phase Ib trial of combining aldoxorubicin plus doxorubicin.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2550-2550
Author(s):  
Kamalesh Kumar Sankhala ◽  
Sant P. Chawla ◽  
Victoria S Chua ◽  
Doris Quon ◽  
Allison Bonk ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Single Agent ◽  
Safety Data ◽  
Tumor Xenograft ◽  
Fixed Dose ◽  
Hematologic Toxicity ◽  
Open Label ◽  
Dose Escalation Study ◽  
Best Response ◽  
Grade 3

2550 Background: Aldoxorubicin is a novel drug that covalently binds to albumin in the circulation with release in low pH environments. Preclinical studies in pancreatic and ovarian tumor xenograft models demonstrated that aldoxorubicin plus doxorubicin administered at 50% of their MTD provided complete and prolonged tumor remission in these models with less toxicity than each drug administered at their MTD. We evaluated the toxicity profile of a fixed dose of doxorubicin and escalating doses of aldoxorubicin in subjects with advanced solid tumors. Methods: Phase 1b open label, dose-escalation study of aldoxorubicin administered at either 175, 240 or 320 mg/m2 (130, 180, or 240 mg/m2 doxorubicin equivalents) iv + 35 mg/m2doxorubicin iv, both on Day 1 of 21 day cycles, for up to 8 cycles. The MTD is the dose level immediately below where 2/6 subjects experience a dose limiting toxicity (DLT) , or the maximum dose of 320 mg/m2aldoxorubicin. Additional subjects may be enrolled at the MTD to provide more safety data. Results: 10 subjects have been treated as of January 21, 2013. No DLT was observed and the MTD was defined as 320 mg/m2 aldoxorubicin and 35 mg/m2 doxorubicin iv administered on Day 1 of 21 day cycles. A median of 4.5 cycles have been received. 3/10 subjects were terminated due to either progressive disease (2) or death (1). No subject was terminated due to an adverse event. Grade 3 or 4 neutropenia was seen at all dose levels (8/10 subjects). 4/10 subjects exhibited grade 3 or 4 thrombocytopenia and 3/10 subjects had grade 3 or 4 anemia. Neutropenic fever occurred in 3/10 subjects. Other grade 3/4 adverse events seen in 2 or fewer subjects included fatigue, increased liver enzymes and dehydration. No significant mucositis or cardiotoxicity was observed. At this time the best response has been stable disease in 6/10 subjects and a partial response in 1 subject (malignant fibrous histiocytoma). Conclusions: The combination of aldoxorubicin (320 mg/m2)) + doxorubicin (35 mg/m2) can be safely administered to subjects with solid tumors. Hematologic toxicity is common and can be controlled with growth factors. The dose of aldoxorubicin is 90% of the MTD of aldoxorubicin administered as a single agent. Thus, doxorubicin does not appear to add to the toxicity of this combination. Clinical trial information: NCT01673438.

scholarly journals An Open-Label, Phase Ib Study of Duvelisib (IPI-145) in Combination with Bendamustine, Rituximab or Bendamustine/Rituximab in Select Subjects with Lymphoma or Chronic Lymphocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4422-4422 ◽  
Author(s):  
Ian Flinn ◽  
Manish R. Patel ◽  
Michael B Maris ◽  
Jeffrey Matous ◽  
Mohamad Cherry ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Febrile Neutropenia ◽  
Phase I ◽  
Dose Escalation ◽  
Research Funding ◽  
Treatment Delay ◽  
Lymphocytic Leukemia ◽  
Open Label ◽  
Grade 3

Abstract Background: Duvelisib is a potent inhibitor of the δ and γ isoforms of phosphoinositide-3-kinase (PI3K) being developed as a potential therapeutic in hematologic malignancies including B and T cell lymphoma and chronic lymphocytic leukemia (CLL). In a phase I study of single agent duvelisib (D), ORR of 52% was seen in pts with indolent non-Hodgkin’s lymphoma (iNHL) and 47% in CLL. Bendamustine (B), rituximab (R), and their combination have demonstrated proven activity in iNHL and CLL. Combining duvelisib with either bendamustine or rituximab alone or in combination with each other may improve response rates and the durability of remission. The goal of this Phase 1b, open-label, three-arm, non-randomized, dose escalating, safety and tolerability trial is to characterize the safety, maximum tolerated dose (MTD) and preliminary efficacy profile of duvelisib given in combination with rituximab (Arm 1-DR), bendamustine plus rituximab (Arm 2-DBR) or bendamustine (Arm 3-DB) in subjects with select relapsed/refractory lymphoma or CLL. Methods: Pts had relapsed CLL or NHL, ECOG performance status (PS) ≤2, and adequate organ function. The subject population during dose escalation was limited to relapsed NHL. During the dose expansion phase, each treatment arm enrolled to population specific cohorts to continue to assess efficacy. Arm 1 (DR) received rituximab 375 mg/m2 IV weekly for 2, 28 day cycles plus duvelisib PO BID up to 12 cycles. Arm 2 (DBR)received rituximab 375 mg/m2 IV weekly for 2, 28 day cycles, bendamustine 90 mg/m2 IV on Days 1 and 2 of the first six cycles plus duvelisib PO BID up to 12 cycles. Arm 3 (DB) received bendamustine 120 mg/m2 IV on Days 1 and 2 of the first six cycles plus duvelisib PO BID up to 12 cycles. Three different dose levels of duvelisib were explored, 25, 50, and 75 mg PO BID. DLTs were defined as: febrile neutropenia, G4 neutropenia ≥7 days, G4 thrombocytopenia ≥ 7 days or G3 thrombocytopenia with bleeding, Grade 4 AST/ALT, Grade 2 hyperbilirubinemia ≥7 days, ≥ Grade 3 non-hematologic toxicity ≥7 days (excluding alopecia), Treatment delay of ≥7 days due to unresolved toxicity that prevents re-dosing, hepatocellular injury (defined as ALT>2 x ULN and (ALT/ULN)/(ALP/ULN) >5) and bilirubin >2 x ULN or jaundice ± alkaline phosphatase <2 x ULN. Patients were evaluated for response every 3 cycles according to specific criteria for their disease. Results: Between August 2013 and May 2014, 32 pts, median age 66 years (44-78) were enrolled to the study, 12 NHL pts on the dose escalation portion and 20 pts on dose expansion (13 CLL, 7 NHL). Patients had a median of 4 prior therapies (1-11). In arms 1 (DR) and 2 (DBR), no dose limiting toxicities were seen at the highest dose level of duvelisib (75 mg bid). In arm 3 (DB) in which a higher dose of bendamustine is used 1 pt developed a DLT at the 50 mg BID dose level of duvelisib (febrile neutropenia, neutropenia ≥ 7 days, thrombocytopenia ≥ 7 days, and liver toxicities which resulted in a treatment delay of ≥ 7 days). Dose escalation continues in this arm as the MTD has not reached. Patients on the dose expansion portion of the study are receiving duvelisib at 25 mg BID due to emerging data of duvelisib monotherapy showing no advantage in doses greater than 25 mg BID in these histologies. The AE profile is consistent with the toxicities of the single agents. The most common AEs > grade 3 were neutropenia (28% overall; [Arm 1 (DR), 27%]; [Arm 2 (DBR), 38%]), and rash (16% overall; [Arm 1, 14%]; [Arm 2, 25%]). Grade 3 or higher AST/ALT increases were seen in 2 out of 12 patients on Arm 1, 2 out of 8 patients on Arm 2 and no patients on Arm 3. There have been 2 deaths (cardiac arrest and pneumonia), both on Arm 1. Twenty one pts were evaluable for response with an ORR of 81% (10% CR, 71% PR, 14% SD and 5% PD). With a median follow up of 4.0 months, time to event analyses are immature. However, Kaplan-Meier estimate of PFS at 3 months is 87%. PK analysis is consistent with the monotherapy Phase I trial of duvelisib. Conclusions: Initial early analysis of duvelisib administered in combination with bendamustine and rituximab suggests these combinations to be generally well-tolerated with encouraging. Further follow-up is required to better characterize response rates and durability of remissions. Disclosures Flinn: Infinity Pharmaceuticals: Research Funding. Matous:Infinity Pharmaceuticals: Research Funding.

Phase II study of neoadjuvant docetaxel and androgen suppression (AS) plus radiation therapy (RT) for high-risk localized prostate cancer (HRLCaP)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4631-4631 ◽  
Author(s):  
M. R. McKenzie ◽  
K. N. Chi ◽  
A. Neville ◽  
S. Ellard ◽  
B. Baerg ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Febrile Neutropenia ◽  
Phase Ii ◽  
Neoadjuvant Treatment ◽  
Hematologic Toxicity ◽  
Open Label ◽  
Genitourinary Toxicity ◽  
Psa Response ◽  
Hormone Refractory ◽  
Grade 3

4631 Background: Docetaxel increases survival in hormone-refractory prostate cancer and is active in hormone-sensitive disease. In HRLCaP, improvement upon AS plus RT is required, as many patients eventually develop metastases. This trial’s objective was to assess the tolerability of neoadjuvant docetaxel plus AS and RT in men with HRLCaP. Methods: Fifty-four men with newly diagnosed previously untreated HRLCaP were accrued to a Phase II single-arm, 2-stage, open-label study involving 7 Canadian centres. All were to receive 3 years of AS (LHRH-agonist + antiandrogen for 4 weeks). Chemotherapy started week 5. Twenty-four men received docetaxel 35 mg m2 iv weekly × 6 q8 weeks for 2 cycles, RT starting week 25. After protocol revision, 30 men received docetaxel 75 mg m2 iv q3 weekly for 4 cycles, RT starting week 21. The primary endpoint was unacceptable toxicity (UT), defined as ≥Grade 3 non-hematologic toxicity (except nausea/vomiting, tearing, short-term fatigue, and easily-controlled diarrhea), grade 4 thrombocytopenia, grade 4 neutropenia lasting >7 days, febrile neutropenia, or toxicity-related RT change (delay>2 weeks, >25% dose reduction). Results: Median age was 68 (49–79) years. Median iPSA was 19.15 (2.8–138) μg/L. Gleason Score and T-stage were ≥8 and ≥T3a in 70.4% and 42.6%, respectively. All patients have completed RT. Adverse events were as expected for docetaxel. UT occurred in 8 patients (14.8%), including 5 with qweekly docetaxel (Grade 3 acute RT-related genitourinary toxicity - 3, Grade 3 docetaxel hypersensitivity - 1, Grade 3 fatigue >2 weeks - 1) and 3 with q3 weekly docetaxel (Grade 3 acute RT-related genitourinary toxicity - 1, febrile neutropenia - 1, Grade 4 neutropenia >7 days - 1). The following table summarizes PSA response to neoadjuvant treatment. Conclusions: Neoadjuvant AS and docetaxel plus RT in men with HRLCaP appeared well tolerated. Patients will be followed for other outcomes. This approach will be tested in a phase 3 trial. [Table: see text] No significant financial relationships to disclose.

Lumiliximab with fludarabine, cyclophosphamide, and rituximab (FCR) for patients with relapsed chronic lymphocytic leukemia (CLL)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6597-6597 ◽  
Author(s):  
S. O’Brien ◽  
J. C. Byrd ◽  
T. J. Kipps ◽  
A. Forero-Torres ◽  
I. W. Flinn ◽  
...  
Keyword(s):  
Safety Profile ◽  
Phase 1 ◽  
Performance Status ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Phase 2 ◽  
Open Label ◽  
Prior Therapy

6597 Background: Lumiliximab, an anti-CD23 monoclonal antibody, had pharmacologic activity and an outstanding safety profile in a recently completed phase 1, single-agent study. Based on evidence of clinical activity, favorable safety profile, and preclinical data suggesting synergy with both fludarabine and rituximab, we initiated a combination study of lumiliximab with FCR in previously treated patients. Methods: Patients ≥18 years of age with relapsed CD23+ B-cell CLL were eligible for this open-label, dose-escalation, phase 1/2 study. Sample size was planned for ≤37 patients. Patients received either 375 mg/m2 or 500 mg/m2 of lumiliximab in combination with each 28-day cycle of FCR for 6 cycles. Primary objectives were to determine the safety profile, recommended phase 2 dose, and clinical activity of lumiliximab with FCR. Results: Accrual began in June 2004; 30 of the 31 patients were enrolled by December 2005; data are available for 28 patients. No dose-limiting toxicity was noted in the phase 1 component (375 mg/m2 dose, n=3, and 500 mg/m2 dose, n=6) and 500 mg/m2 was chosen for the phase 2 dose. All enrolled patients had progressive, symptomatic CLL as defined by NCI criteria, median 2 prior treatments (range, 1 to 9), median age 58, 64% males, 96% WHO performance status of ≤1. Seventeen patients experienced CTC Grade 3 or 4 adverse events (hematologic toxicity typically associated with FCR). Sixteen patients completed ≥3 cycles of treatment and were evaluated for response using NCI-WG criteria: 7 (44%) patients with confirmed complete responses (CRs); 1 with unconfirmed CR (pending marrow confirmation), 3 with partial responses (PRs), 4 with PRs awaiting confirmation, and 1 with disease progression. Twelve patients are not yet evaluable for response. Conclusions: Lumiliximab in combination with FCR is well tolerated and may enhance the activity of FCR for treatment of patients with progressive CLL after prior therapy. [Table: see text]

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