T3 : A Multicenter Phase IB Dose Escalation Study to Evaluate the Safety, Feasibility and Efficacy of the Temsirolimus (Torisel™)-CHOP-Rituximab (T-R-CHOP), Temsirolimus (Torisel™)-FC-Rituximab (T-R-FC) and Temsirolimus (Torisel™)- DHA-Rituximab (T-R-DHA) for the Treatment of Patients with Relapsed/Refractory Mantle Cell Lymphoma (MCL), a Lysa Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4426-4426
Author(s):  
Steven Le Gouill ◽  
Krimo Bouabdallah ◽  
Guillaume Cartron ◽  
Remy Gressin ◽  
Thierry Lamy ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Chemotherapy Regimen ◽  
Cell Lymphoma ◽  
Dose Escalation Study ◽  
Phase Ib ◽  
Multicenter Phase ◽  
Mantle Cell ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract The T3 trial is a multicenter Phase IB dose escalation study that evaluates the safety, feasibility and efficacy of three Temsirolimus-based chemotherapy regimens: Temsirolimus(Torisel™)-CHOP-Rituximab (T-R-CHOP), Temsirolimus(Torisel™)-FC-Rituximab (T-R-FC) and Temsirolimus(Torisel™)-Dexamethasone-aracytine-Rituximab (T-R-DHA) for the treatment of patients with relapsed/refractory Mantle Cell Lymphoma (MCL). The choice of the chemotherapy regimen was left to the decision of local investigator. The primary objective of the T3 was to assess the feasibility and incidence of dose limiting toxicities (DLT) during the two first cycles for each chemotherapy regimen in order to determine the maximal tolerate dose (MTD) in a 3+3 dose escalating design. Dose levels of Temsirolimus (administrated at D2, 8 and 15) were as followed: 25mg level 1; 50mg level 2 and 75mg level 3 and 15 mg in level -1. Patients were planned to receive at least 4 cycles. After 4 cycles, response was evaluated and then patients could continue treatment for 2 additional cycles or receive another treatment according to investigator’s decision. The T3 trial started in November 2011 and so far 38 patients have been enrolled (32 patients are evaluable to date; median age of 69y; range 56 -79). Before inclusion into the T3 trial, patients had received a median of 1 (range 1-3) line of treatment including autologous stem cell transplantation in 15 cases. Nine patients were included in the R-CHOP group (ORR after 4 cycles was 55,6%). In level 1, two patients out of 3 experimented DLT (grade 3: lymphopenia and GI hemorrhage). In level -1 (n=6), one DLT has been reported (grade 3 thrombocytopenia). In the T-R-FC group (n=12; ORR after 4 cycles was 41,7%), 6 patients were included in level 1 and 3 experimented DLT (grade 3: thrombocytopenia and leukopenia). In cohort -1 (n=6), 4 DLTs were reported. Eleven patients were included in the T-R-DHA group (ORR after 4 cycles was 80%). One DLT was suspected during toxicity review in level 1 (n=3) and was not confirmed as a DLT by the Safety Committee, hence the decision to pass to superior dose level. Then 6 patients (3+3) were included in level 2 (50mg) where 1 DLT was reported. However, only one patient received complete schema of temsirolimus with 3 injections because of hematology toxicity. Thus, it has been decided to add 3 additional patients at level 1 (25mg). These patients are currently under treatment. In conclusion, hematological toxicity grade 3 was the major concern of the three temsirolimus-based chemotheprapy regimen. Administration of Temsirolimus at D15 was frequently skipped. However, 51,6% of patients reached at least a PR after 4 cycles and the T-R-DHA group was the safest, in which, 50% of patients reached CR after 4 cycles. Thus, Temsirolimus plus high dose aracytine based-chemotherapy regimens provides good disease control with an acceptable tolerability profile for patients with relapsed MCL. Disclosures Le Gouill: pfizer: Honoraria; mundipharma: Honoraria; roche: Honoraria; celgene: Consultancy, Honoraria; janssen-cilag: Honoraria. Coiffier:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Phase I Dose Escalation Study of Flavopiridol in Combination with Fludarabine and Rituximab: Activity in Indolent B-Cell Lymphoproliferative Disorders and Mantle Cell Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2492-2492
Author(s):  
Thomas S. Lin ◽  
Beth Fischer ◽  
Mollie E. Moran ◽  
David M. Lucas ◽  
Roshini S. Shank ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Lymphoproliferative Disorders ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Mantle Cell ◽  
Grade 3

Abstract The cyclin-dependent kinase inhibitor flavopiridol was inactive when administered as a 72-hour infusion, but a 1-hr IV bolus dosing schedule demonstrated clinical activity in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Flavopiridol induces apoptosis via a p53-independent mechanism. Thus, we hypothesized that flavopiridol may eliminate tumor cells resistant to fludarabine and rituximab. We report preliminary results of an ongoing phase I dose escalation study of flavopiridol in combination with fludarabine and rituximab in patients (pts) with MCL, CLL and other indolent B-cell lymphoproliferative disorders. Pts had adequate marrow function (ANC ≥ 1500, hemoglobin ≥ 9.0, platelets ≥ 100,000), organ function, and performance status (ECOG 0–2) and provided informed consent. Pts in all cohorts received fludarabine 25 mg/m2 IV on days 1–5 and rituximab 375 mg/m2 on day 1 of each 28-day cycle. The planned dose escalation of flavopiridol was 50 mg/m2 by 1-hr IV bolus on day 1 (cohort 1), days 1–2 (cohort 2), or days 1–3 (cohort 3) of each cycle. Treatment was for up to 6 cycles, and pts were placed on prophylactic Bactrim and Valtrex. Fifteen pts have been enrolled to date, and 9 pts are evaluable for toxicity and response. Median age of these 9 pts was 67 years (range, 43–72), and 4 pts were male. Pts had the following diagnoses: CLL (5), MCL (2) and follicular lymphoma (FL; 2). Four pts had received 1–2 prior therapies; 5 pts were previously untreated. CLL pts had Rai stage III/IV disease (2) or required treatment for Rai stage I/II disease (3) by NCI 96 criteria. MCL/FL pts were stage III/IV (3) or had progressive stage II disease (1). Three pts were treated in cohort 1; 2 pts completed 6 cycles, but 1 pt was removed from study after cycle 3 due to prolonged cytopenias. Six pts were treated in cohort 2. Two pts developed dose-limiting toxicity; 1 pt developed grade 3 confusion and grade 3 generalized seizures during cycle 2, and 1 pt developed nausea and diarrhea, which resulted in grade 3 acute renal failure. Infectious toxicity was limited to 1 pt who was hospitalized for 48 hrs with a grade 3 upper respiratory infection and febrile neutropenia. Three pts in cohort 2 were removed from study for prolonged cytopenias after 3, 3 and 4 cycles; only 1 pt in cohort 2 completed 6 cycles. Two of the 6 pts in cohort 2 did not receive flavopiridol after cycles 2 and 3, due to life threatening tumor lysis in our single agent flavopiridol study. Response was graded by NCI 96 criteria (CLL) or IWG criteria (MCL/FL). Overall response rate (ORR) was 100%; 7 pts (78%) achieved CR, and 2 pts achieved PR (22%). Two pts relapsed after 7 and 8 months; 7 pts remain in remission a median of 9 (range,7–12) months after therapy. Of note, all 4 MCL/FL pts remain in CR. An ongoing expansion of 12 pts at the cohort 1 dose level is being conducted, to better define toxicity and efficacy; 6 pts have been enrolled to date. In conclusion, flavopiridol, fludarabine and rituximab exhibited significant clinical activity in a small group of pts, with a 78% CR rate. This combination warrants further study, particularly with consideration to an altered flavopiridol schedule using our highly active 30-minute bolus followed by 4-hour infusion regimen.

scholarly journals ACTR-63. PHASE I DOSE ESCALATION STUDY OF PROCASPASE ACTIVATING COMPOUND-1 (PAC-1) IN COMBINATION WITH TEMOZOLOMIDE IN PATIENTS WITH RECURRENT ANAPLASTIC ASTROCYTOMA OR GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi28-vi28
Author(s):  
Matthias Holdhoff ◽  
Martin Nicholas ◽  
Richard Peterson ◽  
Oana Danciu ◽  
Stefania Maraka ◽  
...  
Keyword(s):  
Dose Level ◽  
Dose Escalation ◽  
Anaplastic Astrocytoma ◽  
Caspase 3 ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Data ◽  
Dose Escalation Study ◽  
Level 1 ◽  
Level 2

Abstract BACKGROUND Procaspase activating compound -1 (PAC-1) is a small molecule that catalyzes conversion of procaspase-3 to caspase-3 which induces apoptosis in cancer cells. Glioblastoma (GBM) is among the tumors with high concentrations of procaspase-3 and low levels of caspase-3. PAC-1 crosses the blood brain barrier and has been shown to synergize with temozolomide (TMZ) in canine malignant glioma and meningioma that arise spontaneously. METHODS This is a multicenter phase 1 dose-escalation study to assess the maximum tolerated dose (MTD) of PAC-1 administered days 1–21 in combination with TMZ days 8–12 at a dose of 150 mg/m2 of each 28 day cycle in subjects with recurrent anaplastic astrocytoma (AA) or GBM. A modified Fibonacci 3 + 3 design is used with up to 4 dose levels of PAC-1 (375, 500, 625 and 750 mg/day). Neurologic toxicity, including cognitive function, is closely monitored throughout the trial. INTERIM DATA: A total of 14 subjects have been enrolled to-date. Of these, 7 at dose level 1, PAC-1 375 mg/day (6 GBM, 1 AA; median age 58y, range 25–75) and 7 at dose level 2, PAC-1 500 mg/day (5 GBM, 2 AA; median age 51y, range 35–60). Best responses to-date were 2 subjects with a partial response and 2 with stable disease. Grade 3 (hepatotoxicity) and 4 (cerebral edema) was reported as possibly related to PAC-1 in 1 patient at dose level 1. The median number of cycles received was 4 (range, 1–12+) at dose level 1 and 2 (range, 1–3) at dose level 2. Enrollment to dose level 2 has been completed and data analysis is ongoing. Updated response and toxicity as well as pharmacokinetic data will be presented.

Preliminary Safety and Efficacy of the Combination of Brentuximab Vedotin and Ipilimumab in Relapsed/Refractory Hodgkin Lymphoma: A Trial of the ECOG-ACRIN Cancer Research Group (E4412)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 585-585 ◽  
Author(s):  
Catherine S. Diefenbach ◽  
Fangxin Hong ◽  
Jonathon B. Cohen ◽  
Michael J. Robertson ◽  
Richard F. Ambinder ◽  
...  
Keyword(s):  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Checkpoint Inhibitor ◽  
Sensory Neuropathy ◽  
Peripheral Sensory Neuropathy ◽  
Level 1 ◽  
Grade 3 ◽  
Peripheral Sensory ◽  
Level 2

Abstract Background: Despite advances in chemotherapy, R/R HL remains a significant clinical problem with over 1,000 primarily young lives lost annually. HL is a unique tumor in which a small number of malignant Hodgkin Reed-Sternberg (HRS) cells propagate an immunosuppressive microenvironment that augments HRS growth and survival. We hypothesized that immune checkpoint inhibitor therapy could activate the tumor immune microenvironment, while the CD30 expressing HRS cells could be targeted by brentuximab vedotin (BV), thereby overcoming tumor cell resistance and deepening clinical responses. E4412 is a phase 1 ECOG-ACRIN sponsored study of the combination of BV and the checkpoint inhibitors ipilimumab (IPI) and nivolumab (NIVO) in patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL). Here we report the data on the patients treated with BV + IPI, the first cohort of the study. Methods: Patients with biopsy proven R/R HL were treated with BV 1.8mg/kg and two escalating doses of IPI: 1 mg/kg or 3mg/kg. After safety was determined an expanded cohort was treated with BV 1.8mg/kg IV and IPI 3mg/kg IV. The schedule consisted of BV administered every 21 days for 16 cycles and IPI every 21 days x 4 doses and thereafter every 3 months for up to a year. Dose limiting toxicity (DLT) was defined for purposes of dose escalation within the first cycle of therapy. Patients are followed for toxicity up to 30 days beyond their last treatment. Results: As of 7/2015 19 of 23 planned patients have been treated with BV + IPI. We report the data on the full dose escalation population (13 patients: Dose level 1 (6), Dose level 2 (7)). The median age was 33 years (range: 20-49). Seven patients were male. Patients were heavily pretreated with a median of 4 prior therapies (2-13). Fourpatients had prior treatment with BV; 8 patients had prior SCT (7 autologous, 1 allogeneic). Safety: Overall the regimen of BV + IPI was extremely well tolerated with no DLTs noted during dose escalation. Toxicities considered at least possibly related to drug during any cycle of treatment are shown according to grade in Table 1. The most common treatment related adverse events were: diarrhea, rash, and peripheral sensory neuropathy. Other AEs of interest included: alopecia, transaminitis, and uveitis. Grade 3 and 4 treatment related adverse events (AEs) included: Dose level 1: one grade 3 infusion reaction, which led to a protocol amendment to include premedication, no further grade 3 infusion reactions were noted; Dose level 2: one each: grade 3 rash, vomiting, and peripheral sensory neuropathy, and one grade 4 thrombocytopenia in patient with pre-existing thrombocytopenia. Response: For the 12 evaluable patients, the overall response (ORR) for the combination of BV + IPI was 67% with a complete response (CR) rate of 42% (5 of 12 patients). An additional 2 patients had stable disease (SD) giving a clinical benefit rate of 83%. Three of 5 of the CRs occurred at dose level 1 (1mg dose of IPI). The median progression free survival (PFS) is 0.74 years with a median follow-up of 0.66 years. Conclusion: In this first reported study of the combination of checkpoint inhibitor and ADC, toxicity was low, primarily grades 1 and 2. In a heavily pretreated patient population, 33% of whom had had prior BV and 67% of whom were s/p ASCT, the ORR of 67% and CR rate of 42% suggests a potential deepening of response compared to monotherapy. More than half of these CRs occurred at 1mg of IPI suggesting that in combination with ADC, low doses of immune stimulation may be highly active. Optimization of this combination strategy is planned with ongoing accrual to cohorts receiving BV + NIVO, and BV + IPI + NIVO. Data will be updated to include the full BV + IPI cohort by the time of the annual meeting. Table 1. Common and Immune Toxicities Toxicity Type Dose Level 1 (n=6) Dose Level 2 (n=7) Grade Grade 1,2 3 4 5 1,2 3 4 5 (n) (n) (n) (n) (n) (n) (n) (n) Fatigue 5 - - - 3 - - - Fever 1 - - - 3 - - - Pain 2 - - - 3 - - - Alopecia 2 - - - 1 - - - Pruritus 1 - - - 2 - - - Rash maculo-papular 4 - - - 2 1 - - Diarrhea 4 - - - 4 - - - Dyspepsia 2 - - - 1 - - - Nausea 6 - - - 4 - - - Vomiting 3 - - - 2 1 - - Papulopustular rash 1 - - - 1 - - - Alanine aminotransferase increased 3 - - - 3 - - - Aspartate aminotransferase increased 3 - - - 2 - - - Platelet count decreased - - - - - - 1 - Anorexia 3 - - - - - - - Headache 2 - - - 2 - - - Peripheral sensory neuropathy 5 - - - 4 1 - - Dry eye 2 - - - - - - - Uveitis 1 - - - - - - - Cough 2 - - - 1 - - - Disclosures Diefenbach: Molecular Templates: Research Funding; Immunogen: Consultancy; Celgene: Consultancy; Idera: Consultancy; Jannsen Oncology: Consultancy; Gilead: Equity Ownership, Research Funding, Speakers Bureau; Incyte: Research Funding; Genentech: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Off Label Use: Presentation will discuss the experimental use of the checkpoint inhibitor Ipilimumab in relapsed/refractory Hodgkin lymphoma.. Cohen:Celgene: Consultancy; Millennium: Consultancy; Pharmacyclics: Consultancy; Seattle Genetics: Consultancy; BMS: Research Funding; Janssen: Research Funding. Robertson:Eli Lilly: Equity Ownership. Fenske:Pharmacyclics: Honoraria; Seattle Genetics: Honoraria; Millennium/Takeda: Research Funding; Celgene: Honoraria. Kahl:Roche/Genentech: Consultancy; Seattle Genetics: Consultancy; Millennium: Consultancy; Cell Therapeutics: Consultancy; Celgene: Consultancy; Infinity: Consultancy; Pharmacyclics: Consultancy; Juno: Consultancy. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding.

Phase I study of vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients (pts) with non-Hodgkin lymphoma (NHL) in Japan

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18521-18521 ◽  
Author(s):  
K. Tobinai ◽  
T. Watanabe ◽  
Y. Kobayashi ◽  
S. Yamasaki ◽  
Y. Morita-Hoshi ◽  
...  
Keyword(s):  
Phase I ◽  
Cell Lymphoma ◽  
International Workshop ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Non Hodgkin Lymphoma ◽  
T Cell Lymphomas ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

18521 Background: Vorinostat (Zolinza™), a potent histone deacetylase inhibitor, has demonstrated clinical activity in pts with cutaneous T-cell lymphomas (CTCL) and other NHL subtypes. However, the clinical activity and PK profile in Japanese pts with NHL was unknown. Methods: Japanese pts with NHL were sequentially enrolled in two dose levels ranged from 100 (Level 1) - 200 mg (Level 2) BID, PO for 14 consecutive days every 3 wks. Higher doses were not tested as other phase I studies had established that 300 mg BID for 14 consecutive days every 3 wks exceeded the MTD. PK profiles were analyzed in serum and urine samples. Response was also evaluated according to the international workshop criteria. Results: Ten pts were enrolled: 9 were evaluable for toxicity. One was excluded due to noncompletion of the 1st cycle. All were evaluable for PK. Median age was 60 yrs (range 52–74). Four pts had follicular lymphoma (FL), 2 mantle cell lymphoma (MCL), 2 diffuse large B-cell lymphoma and 2 CTCL. Median no. of prior regimens was 3 (1–4). In the 1st cycle, none of 3 pts at Level 1 and 1 of 6 pts at Level 2 developed DLTs (anorexia and hypokalemia of grade 3), indicating Level 2 to be the MTD in this setting. PK was not greatly affected by multiple doses. Intact drug was hardly excreted in urine (<1% of dose). PK profile is similar to that established in US pts. As of Dec 2006, 4 pts were continuing treatment (median 5 mos [1–15]). Two pts with FL showed PR for 8+ and 2+ mos, respectively, and the remaining 1 pt with FL and 1 of 2 pts with MCL showed tumor reduction greater than 30%. Conclusions: Oral vorinostat was well tolerated up to 200 mg BID for 14 consecutive days every 3 wks in Japanese pts with NHL. Preliminary observations of clinical efficacy warrant further investigations for NHL focusing on FL and MCL. No significant financial relationships to disclose.

MLN9708, an investigational proteasome inhibitor, in patients (pts) with relapsed/refractory lymphoma: Emerging data from a phase I dose-escalation study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8064-8064 ◽  
Author(s):  
Peter Martin ◽  
Julie E. Chang ◽  
Robert M. Rifkin ◽  
Ai-Min Hui ◽  
Deborah Berg ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Proteasome Inhibitor ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
20S Proteasome ◽  
Multiple Time ◽  
Cell Transplant ◽  
Dose Escalation Study ◽  
Refractory Lymphoma ◽  
Grade 3

8064 Background: MLN9708 is a reversible, orally bioavailable, specific 20S proteasome inhibitor. This study (NCT00893464) studied the safety and determined the MTD of IV MLN9708 in pts with relapsed/refractory lymphoma, and characterized pharmacokinetics (PK) and pharmacodynamics (PD). Methods: Pts aged ≥18 yrs who had failed ≥2 chemotherapeutic regimens received IV MLN9708 on days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. One pt was enrolled at the 0.125 mg/m2 starting dose; dose doubling proceeded with 1 pt at each dose up to 1.0 mg/m2. Dose escalation occurred in ≤40% increments using a standard 3+3 scheme based on DLT occurrence in cycle 1. Blood samples were collected at multiple time points after dosing on days 1 and 15 of cycle 1 for PK/PD analyses. Results: At data cut-off (Dec 1 2011), 21 pts had been enrolled and treated: 1 each at 0.125, 0.25, 0.5 and 1 mg/m2, 4 at 1.4 mg/m2, 7 at 1.76 mg/m2, and 6 at 2.34 mg/m2. Median age was 57 yrs (range 23–78); 57% were male. Median number of prior therapies was 5; 29% had prior radiation, 24% prior stem cell transplant. Histologies included T-cell lymphoma (n=5), Hodgkin lymphoma (n=3), follicular lymphoma (n=2), DLBCL (n=1) and other indolent B-cell lymphoma (n=7). Pts had received a median of 2 cycles (range 1–22); 2 DLTs were seen (neutropenia at 1.76 and 2.34 mg/m2). All pts experienced drug-related AEs, including fatigue (48%), nausea (29%), diarrhea (29%), pyrexia, thrombocytopenia, and vomiting (each 24%). 43% had drug-related grade ≥3 AEs, 1 pt discontinued due to drug-related grade 3 neutropenia (2.34 mg/m2). Three pts had drug-related peripheral neuropathy (1 grade 1, 2 grade 2). There were no on-study deaths. Of 18 response-evaluable pts, 3 achieved PR (including 2 who remain in response and on-study for >1 yr) and 4 SD. PK analyses showed linear PK (0.5–2.34 mg/m2) and a terminal half-life of ~6–9 days. There was a dose-dependent increase in maximal whole blood 20S proteasome inhibition. Conclusions: These data suggest IV MLN9708 is generally well tolerated, with infrequent PN, and is clinically active in pretreated lymphoma pts. The trial is ongoing and updated data will be presented.

scholarly journals Pralatrexate in Combination with Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP) in Previously Untreated Patients with Peripheral T-Cell Lymphoma (PTCL): A Phase 1 Dose-Escalation Study

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 818-818 ◽  
Author(s):  
Andrei Shustov ◽  
Patrick B Johnston ◽  
Stefan Klaus Barta ◽  
Gajanan Bhat ◽  
Guru Reddy ◽  
...  
Keyword(s):  
T Cell ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
T Cell Lymphoma ◽  
Peripheral T Cell Lymphoma ◽  
Dose Escalation Study ◽  
Chop Regimen ◽  
Treatment Naïve ◽  
Grade 3

Abstract Background: The prognosis of patients with PTCL remains poor after standard CHOP therapy - the most commonly used combination regimen. Relapses occur in the majority of patients, and curability rates of the relapsed disease are very low. Hence, advances in front-line therapy of PTCL are long overdue. Pralatrexate, a second-generation antifolate, demonstrated a single agent activity in patients with relapsed and refractory PTCL with a response rate of 27%, including complete remissions in 11% of patients (O'Connor et al. J Clin Onc 2011). We conducted a Phase 1 multi-center dose-escalation study of pralatrexate in combination with standard CHOP (Fol-CHOP) in treatment-naïve PTCL patients. Objectives: The primary objective of the study was to determine the maximum tolerated dose (MTD) of pralatrexate when administered with a standard CHOP regimen to patients with newly diagnosed PTCL. The secondary objectives included safety, tolerability, efficacy and pharmacokinetics of pralatrexate in combination with CHOP (Fol-CHOP). Methods: In Part 1 of this 3+3 dose-escalation study, pralatrexate was administered at 10, 15, 20, 25, or 30 mg/m2 as an IV push on days 1 and 8 of a standard 21-day CHOP regimen (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 [maximum 2 mg] on day 1 and oral prednisone 100 mg on days 1-5). In Part 2 of the study patients were treated at the MTD of pralatrexate established in Part 1, with standard CHOP. In both parts of the study patients were treated with up to 6 cycles of therapy, or until toxicity or disease progression. Patients received antimicrobial prophylaxis, myeloid growth factor support, and "leucovorin rescue" throughout 6 cycles of therapy. Dose-limiting toxicities (DLT) were considered during the 1st cycle of Fol-CHOP and included: Grade 4 infections, treatment-related non-hematological toxicity ≥Grade 3, platelet count &lt; 25 X 109/L at any time, or ANC &lt; 0.5 X 109/L for &gt;7 days despite G-CSF administration. Responses were assessed by the investigator per the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results: A total of 31 patients have been enrolled (19 in Part 1; 12 in Part 2). MTD was not reached and pralatrexate dose of 30 mg/m2 in combination with CHOP was selected for Part 2 of the study as predefined by the protocol. The majority of patients were male, White, with the median age of 66 yrs (range, 18-78) at the time of enrolment. PTCL diagnoses included: anaplastic large cell lymphoma, anaplastic lymphomakinase-negative (ALCL, ALK-, n=5), peripheral T-cell lymphoma, not-otherwise specified (PTCL-NOS, n=18), and angioimmunoblastic T-cell lymphoma (AITL, n=5). Fol-CHOP was generally well tolerated with median RDI of 98%. Common (≥ 30%) adverse events (AEs) of any grade were fatigue (n=23), constipation (n=20), nausea (n=16), mucositis (n=14), diarrhea (n=12), anemia (n=9), vomiting (n=10) and oral pain (n=10). Most common (≥ 10%) AEs ≥ grade 3 were anemia (n=6), fatigue (n=4) and neutrophil count decreas (n=5). The only Grade &gt;3 treatment-related AEs (≥10%) was neutrophil count decrease (n=4). SAEs were observed in 13 patients, treatment related SAEs were anemia, febrile neutropenia, dehydration, mucositis and nausea. Five patients withdrew from study: 2 due to disease progression, 1 due to AE and 2 due lapse &gt;28 days between doses. In the 27 patients avaluable for response, the investigator assessed objective response (OR) and complete response (CR) rates were 89% wand 67%, respectively. Conclusions: The combination of pralatrexate and CHOP was well tolerated in treatment-naive PTCL patients. MTD of pralatrexate was not reached, and the protocol-defined maximum dose of 30 mg/m2 on days 1 and 8 of a 21-day CHOP cycle was recomended for future studies. The observed OR and CR rates warrant further evaluation of this regimen in newly diagnosed PTCL patients. Disclosures Shustov: Celgene: Other: Publication assistance; Spectrum Pharmaceuticals: Consultancy, Research Funding. Bhat: Spectrum Pharmaceuticals: Employment. Reddy: Spectrum Pharmaceuticals: Employment.

scholarly journals The Results of a Phase I Study using Velcade (Bortezomib), Cladribine, and Rituximab (VCR) in treating Mantle Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1792-1792 ◽  
Author(s):  
Jeffrey J. Pu ◽  
W. Christopher Ehmann ◽  
Jason Liao ◽  
Christine Capper ◽  
Michelle Levy ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
B Cell ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Newly Diagnosed ◽  
Phase 1 Study ◽  
Mantle Cell ◽  
Level 3 ◽  
Level 1

Abstract Background: Mantle cell lymphoma (MCL) is a moderately aggressive and incurable small to medium size B cell lymphoma. There is no standardized treatment for this disease. The conventional chemotherapy results in a high incidence of treatment related toxicity with frequent disease relapse. Cladribine is a hypomethylating agent that indirectly downregulate DNA methylation to suppress tumorigenesis. Combination of Cladribine and Rituximab showed a synergetic effect in treating B cell lymphomas. Velcade (Bortezomib) is a FDA approved proteasome inhibitor to treat relapsed/refractory MCL. In this phase 1 study, we evaluated the safety and efficiency of Valcade, Cladribine, and Rituximab (VCR) combination treatment in newly diagnosed and relapsed/refractory MCL. Patients and Methods: This is a single arm, open label, investigator initiated Phase 1 study conducted at PennState Hershey Cancer Institute. This study employed a standard 3+3 dose-escalation scheme designed to determine the maximum tolerated dose (MTD) of Cladribine in VCR regimen. The treatment scheme and Cladribine dose escalation levels (1, 2, and 3) are as follows: the therapy consisted of 6 28-day cycles. At first cycle of the treatment, Rituximab 375 mg/m2 infusion started on day 5 of the first week and then given weekly for 3 weeks; in the next 5 cycles Rituximab was given on day 5 of each cycle, and then every 2 months as the maintenance therapy. Cladribine 3-5 mg/m2 (3 mg/m2 for level 1, 4 mg/m2 for level 2, and 5 mg/m2 for level 3) infusion was given on days 1-5 for 6 cycles. If the patient's was older than 70 years old, Cladribine was only given on days 1-3 of each cycle. Velcade 1.6 mg/m2 subcutaneous injection was given on days 12, 19 and 26 for cycles 1-3, then Day 5 and 19 during Cycles 4-6, then once per month as maintenance therapy until toxicity or progression of the disease. The primary endpoint of this study was to investigate the dose-limiting toxicity (DLT), safety, and efficiency of this regimen in patients with MCL. The secondary endpoints included remission rate (RR), progression-free survival (PFS) and overall survival (OS). The analysis was done by intent to treat. This study is registered with clinicaltrials.gov (NCT01439750). Results: No subject experienced dose limited toxicity (DLT) at either level 1 or 2, one possible DLT (infectious colitis) was observed on a subject during 2nd cycle at level 3. Then no additional DLTs were seen in 3 subjects added to level 3. Overall, this study recruited 13 subjects, with a median age of 64 years old (range from 55 to 83), and a total of 11 male and 2 females. Ten subjects were never previously treated, while 3 either relapsed or failed previous treatments. The majority of subjects tolerated this regimen well. The patient with a history of DLT became the only mortality of this cohort 7 months later as a result of multiple organ failure. The overall remission (OR) rate was 85% (11/13) and complete remission (CR) rate was 62% (8/13). In newly diagnosed subject cohort, the RR and OS rates were 100% (9/9), PFR was 89% (8/9), and CR rate was 78% (7/9), of which 2 patients have been followed for more than 3 years and 4 patients for more than 2 years. However, in relapsed/refractory subject cohort, 1 subject achieved CR for 7 months but then relapsed, 2 subjects had no response. There were 2 blastoid subjects, one was newly diagnosed and achieved CR. No severe systemic toxicity was observed in this study. Bone marrow suppression caused prolonged anemia and thrombocytopenia were the most common toxicity (3/13 with ≤grade 2). Low grade peripheral neuropathies (≤grade 2) were observed in 15% (2/13). Mild fatigue was a frequent complaint. Correlative studies measured cyclin D1 expression levels using mononuclear cells as opposed to formalin-preserved tissue, a technique which allows for monitoring the levels over time. Although limited by a small sample size, the results indicated that the G/G (or A/A) genotype at G870A polymorphism site as well as a rapid decline of cyclin D1 and D1a during treatment may be correlated to a less aggressive disease course. Further studies are needed to explore the underlining mechanism. Conclusions: The VCR combination is a well tolerated, low toxicity and effective regimen for MCL, especially for untreated MCL. Cladribine 5 mg/m2 is a tolerable dose with manageable toxicity. A phase II trial to further evaluate the activity and toxicity of VCR regimen is warranted. Disclosures No relevant conflicts of interest to declare.

A phase Ib study of second-line therapy with panitumumab, irinotecan, and everolimus (PIE) in metastatic colorectal cancer (mCRC) with KRAS wild type (WT).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e14506-e14506 ◽  
Author(s):  
Amanda Rose Townsend ◽  
Louise Pirc ◽  
Pamela Cooper ◽  
Niall C. Tebbutt ◽  
Christos Stelios Karapetis ◽  
...  
Keyword(s):  
Dose Level ◽  
Mammalian Target Of Rapamycin ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Treatment Delays ◽  
Phase Ib ◽  
Combination Methods ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

e14506 Background: The mammalian target of rapamycin (mTOR) is a key downstream protein activated via PI3K-AKT pathway, and regulates cell growth, proliferation, and survival. Inhibition of mTOR in addition to EGFR may overcome upstream resistance to EGFR inhibitors in CRC. This is a phase Ib study to determine the maximum tolerated dose (MTD) of the PIE combination. Methods: Patients with KRAS WT mCRC following failure of first line fluoropyrimidine based therapy received IV irinotecan and panitumumab every 2 weeks, and everolimus orally throughout a 14 day cycle. Dose finding used a standard 3+3 design with the MTD defined as the dose with dose limiting toxicity (DLT) in ≤1/6 patients. A DLT is any of the following in the first 28 days; febrile neutropenia, G3/G4 neutropenia > 14 days, any G4 thrombocytopenia, any non-haematologic event of G4 or of G3 for >7 days, treatment delays of >14 days. Dose level 1; irinotecan 200mg/m2, panitumumab 6mg/kg, everolimus 5mg alternate days. Dose level 2; irinotecan 200mg/m2, panitumumab 6mg/kg, and everolimus 5mg daily. Results: 15 patients have been enrolled into the study, 2 withdrew prior to receiving any therapy. Five patients were enrolled at dose level 1. Two patients were not evaluable. Of the three evaluable patients there was no DLT. Three patients were then treated at dose level 2. Following one DLT (grade 3 mucositis >7 days), the cohort was expanded to 5 evaluable patients but suspended after a further DLT (grade 3 mucositis > 7 days). Other grade 3 toxicities were anorexia, rash, vomiting, and hypersensitivity. There were no grade 4 toxicities. Dose level 1 was expanded by 3, to a total of 6 evaluable patients. Grade 3 toxicities were mucositis (17%), fatigue (17%), diarrhoea (33%), rash (17%), hypomagnesemia (17%), and neutropenia (17%). There was no DLT. Conclusions: Dose level 2 exceeded the MTD. Dose level 1 appears tolerable and warrants further investigation. The phase II component of the study is ongoing. Clinical trial information: NCT01139138.

Phase Ib study of MIW815 (ADU-S100) in combination with spartalizumab (PDR001) in patients (pts) with advanced/metastatic solid tumors or lymphomas.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2507-2507 ◽  
Author(s):  
Funda Meric-Bernstam ◽  
Shahneen Kaur Sandhu ◽  
Omid Hamid ◽  
Anna Spreafico ◽  
Stefan Kasper ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Checkpoint Inhibitors ◽  
Dose Schedule ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Dose Escalation Study ◽  
Phase Ib ◽  
Grade 3 ◽  
Sting Pathway

2507 Background: MIW815 (ADU-S100) is a novel synthetic cyclic dinucleotide that activates the STimulator of INterferon Genes (STING) pathway impacting tumor cells, tumor microenvironment, vasculature, tumor-associated fibroblasts, and priming APC and CD8+ T cells. Spartalizumab is a humanized IgG4 mAb that blocks the binding of PD-1 to PD-L1/2. Preclinical data support synergistic antitumor effects when MIW815 (ADU-S100) is combined with checkpoint inhibitors. Methods: In this Phase Ib dose escalation study, pts with advanced/metastatic solid tumors or lymphoma received MIW815 (ADU-S100) (intratumoral injections [50–800 µg] either weekly [3 weeks on/1 week off] or Q4W) and spartalizumab (400 mg IV Q4W). Injected and non-injected tumor biopsies were obtained at baseline and on treatment. Primary objectives are to determine safety and identify a dose/schedule for future studies. Preliminary activity, pharmacokinetics (PK), and pharmacodynamics (PD) are also being explored. Results: As of Jan 11, 2019, 66 pts (median age: 61 y) with various solid tumors or lymphomas have been treated. Treatment was discontinued in 49 pts (74%) due to disease progression (n = 28), pt/physician decision (n = 18), AE (n = 2), or death (n = 1). No DLTs were reported during the first cycle at any dose level. Most common (≥5 pts) treatment-related AEs (TRAEs) were injection site pain (12%), pyrexia (11%), and diarrhea (9%). Grade 3/4 TRAEs (in ≥2 pts) were increased AST and ALT (3% each). Serious TRAEs were pyrexia (3%), increased amylase, increased lipase, diarrhea, fatigue, hyperthyroidism, partial seizures, dyspnea, and pneumonitis (all 2%). Partial responses in pts with PD-1–naive TNBC and PD-1–relapsed/refractory melanoma have been observed. MIW815 (ADU-S100) plasma exposure generally increased in a dose-dependent manner with a rapid terminal half-life. Response data, PK and PD analyses will be presented. Conclusions: Thus far, MIW815 (ADU-S100) + spartalizumab has demonstrated antitumor activity in PD-1–naive TNBC and PD-1–relapsed/refractory melanoma. The combination is well tolerated, with no DLTs reported to date. The MTD has not been reached and dose escalation is ongoing. Clinical trial information: NCT03172936.

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