Australasian Gastrointestinal Trials Group (AGITG) CONTROL NET Study: Phase II study evaluating the activity of 177Lu-Octreotate peptide receptor radionuclide therapy (LuTate PRRT) and capecitabine, temozolomide CAPTEM)—First results for pancreas and updated midgut neuroendocrine tumors (pNETS, mNETS).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4608-4608
Author(s):  
Nick Pavlakis ◽  
David Turner Ransom ◽  
David Wyld ◽  
Katrin Marie Sjoquist ◽  
Rebecca Asher ◽  
...  
Keyword(s):  
Phase Ii ◽  
Single Agent ◽  
Tumour Response ◽  
Peptide Receptor Radionuclide Therapy ◽  
Relative Activity ◽  
Phase Iii ◽  
Study Phase ◽  
Open Label ◽  
Who Grade

4608 Background: CAPTEM is an accepted regimen for patients (pts) with advanced pNETs. Single agent 177Lu-Octreotate PRRT is now a standard of care for progressive WHO Grade (G) 1/2 mNETs. High activity was seen with LuTate/CAPTEM in a single arm Phase I/II trial. This study was undertaken to determine the relative activity of adding CAPTEM to LuTate PRRT in pts with mNETs and pNETs. Methods: Non-comparative randomised open label parallel group phase II trial with 2:1 randomisation to PRRT/CAPTEM (experimental arm) vs. PRRT (mNETs control) and CAPTEM (pNETS control). PRRT/CAPTEM: 7.8GBq LuTate day(D) 10, 8 weekly (wkly) x 4, with b.i.d. oral CAP 750mg/m2 D1-14 & TEM 75mg/m2D10-14, 8 wkly x 4; PRRT: 8 wkly x 4; CAPTEM 8 wkly x 4. Primary endpoint: Progression free survival (PFS). mNETS- at 15 months (mo) assuming 15mo PFS 66.4% in control arm, aiming for PFS ³ 80%; pNETS- at 12mo assuming 12mo PFS 60% in control arm, aiming for PFS ³ 75%. Secondary endpoints: Objective tumour response rate (complete or partial) (OTRR), clinical benefit rate (OTRR, stable disease) (CBR), toxicity, quality of life. Results: 75 pts enrolled (Dec 2015 – Nov 2018): mNETs 33 PRRT/CAPTEM and 14 PRRT; pNETS 19 PRRT/CAPTEM and 9 CAPTEM. mNETS: Median follow-up 35mo; 15mo PFS was 90% (95% CI: 73-97%) v 92% (95% CI: 57-99%); OTRR 31% vs 15%; and CBR 97% vs 92% for PRRT/CAPTEM v PRRT respectively. Treatment related adverse events (AEs): 24/32 PRRT/CAPTEM pts had at least one G3 event (75%) vs 5/13 (38%, PRRT); and 4/32 pts at least one G4 event (13%) v 1/13 (8%) respectively, mostly haematologic (haem). Only one patient failed to complete therapy (PRRT/CAPTEM). pNETS: Median follow-up 34mo; 12mo PFS was 76% (95% CI: 48-90%) v 67% (95% CI: 28-88%); OTRR 68% vs 33%; and CBR 100% vs 100% for PRRT/CAPTEM v CAPTEM respectively. Treatment related AEs: 5/18 PRRT/CAPTEM pts had at least one G3 event (28%) vs 3/9 (33%) CAPTEM; 3/18 pts at least one G4 event (17%) v 1/9 (11%) respectively. Conclusions: CAPTEM/PRRT is active, meeting its target landmark PFS for CAPTEM/PRRT (12mo pNETs; 15mo mNETs) with numerically greater OTRR in both pNETs and mNETs, but with more haem toxicity in mNETs. As activity was high in both control arms longer follow up is required to determine if the relative activity of PRRT/CAPTEM is sufficient to warrant Phase III evaluation. Clinical trial information: ACTRN12615000909527 .

First results for Australasian Gastrointestinal Trials Group (AGITG) control net study: Phase II study of 177Lu-octreotate peptide receptor radionuclide therapy (LuTate PRRT) +/- capecitabine, temozolomide (CAPTEM) for midgut neuroendocrine tumors (mNETs).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 604-604 ◽  
Author(s):  
Nick Pavlakis ◽  
David Turner Ransom ◽  
David Wyld ◽  
Katrin Marie Sjoquist ◽  
Rebecca Asher ◽  
...  
Keyword(s):  
Partial Response ◽  
Phase Ii ◽  
Radionuclide Therapy ◽  
Single Agent ◽  
Tumour Response ◽  
Peptide Receptor Radionuclide Therapy ◽  
Phase Iii ◽  
Study Phase ◽  
Peptide Receptor

604 Background: Single agent 177Lu-octreotate peptide receptor radionuclide therapy is now a standard of care for progressive mNETS. High activity was seen with LuTate and concurrent CAPTEM chemotherapy in a single arm Phase I/II trial. This study was undertaken to determine the relative activity of adding CAPTEM to LuTate PRRT in patients with mNETs. Methods: Non-comparative randomised open label phase II trial of PRRT +/- CAPTEM in patients with mNETs, with 2:1 randomisation: PRRT /CAPTEM (experimental arm) vs. PRRT (control). PRRT /CAPTEM: 7.8GBq LuTate day(D) 10, 8 weekly (wkly) x 4, with b.i.d. oral CAP 750mg/m2 D1-14 & TEM 75mg/m2 D10-14, 8 wkly x 4, vs. PRRT 8 wkly x 4. Primary endpoint: progression free survival (PFS) at 15 months assuming 15 month PFS of 66.4% in the control arm, aiming for PFS rate > 80%; secondary endpoints: objective tumour response rate (complete or partial response) (OTRR), clinical benefit rate (complete or partial response, stable disease) (CBR), toxicity, and QOL. Results: 47 patients enrolled (Dec 2015 - Feb 2018): 33 PRRT/CAPTEM and 14 PRRT. Two patients withdrew prior to treatment. Patient characteristics were balanced except gender (female 58% vs. 14%). Two patients received 2 prior systemic regimens. After a median follow-up of 32 months, the 15 month PFS was 90% (95% CI: 73-97%) v 92% (95% CI: 57-99%); OTRR 25% vs 15%; and CBR 97% vs 92% for PRRT/CAPTEM v PRRT respectively. For treatment related adverse events 22/32 CAPTEM patients experienced one Grade 3 event (69%) vs 5/13 (38%, PRRT); 4/32 pts experienced one Grade 4 event (13%) v 1/13 (8%) respectively. Only one patient failed to complete therapy due to toxicity (PRRT/CAPTEM). Conclusions: This initial planned analysis demonstrates similarly high 15 month PFS for CAPTEM/PRRT relative to PRRT alone. OTRR is numerically higher but at the cost of greater toxicity. Longer follow up is required to determine if the activity of PRRT/CAPTEM is sufficient to warrant Phase III evaluation. Clinical trial information: ACTRN12615000909527.

scholarly journals Oral levosimendan in amyotrophic lateral sclerosis: a phase II multicentre, randomised, double-blind, placebo-controlled trial

2019 ◽  
Vol 90 (10) ◽  
pp. 1165-1170 ◽  
Author(s):  
Ammar Al-Chalabi ◽  
Pamela Shaw ◽  
P Nigel Leigh ◽  
Leonard van den Berg ◽  
Orla Hardiman ◽  
...  
Keyword(s):  
Heart Rate ◽  
Amyotrophic Lateral Sclerosis ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Phase Iii ◽  
Open Label ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Lateral Sclerosis

ObjectiveTo evaluate the efficacy and safety of oral levosimendan in patients with amyotrophic lateral sclerosis (ALS). This phase II, randomised, double-blind, placebo-controlled, crossover, three-period study with 6 months open-label follow-up enrolled adults with ALS and sitting slow vital capacity (SVC) 60%–90 % of predicted from 11 sites in four countries.MethodsPatients received levosimendan 1 mg daily, 1 mg two times a day or placebo during three 14-day crossover periods and levosimendan 1–2 mg daily during open-label follow-up. Primary endpoint was sitting SVC; secondary endpoints included supine SVC, ALS Functional Rating Scale-Revised (ALSFRS-R), tolerability and safety.ResultsOf 66 patients randomised, 59 contributed to the double-blind results and 50 entered open-label follow-up. Sitting SVC was not significantly different between the treatments. In post hoc analysis using period-wise baselines, supine SVC favoured levosimendan over placebo, estimated mean differences from baseline being −3.62% on placebo, +0.77% on levosimendan 1 mg daily (p=0.018) and +2.38% on 1 mg two times a day (p=0.001). Headache occurred in 16.7% of patients during levosimendan 1 mg daily (p=0.030), 28.6% during 1 mg two times a day (p=0.002) and 3.3% during placebo. The respective frequencies for increased heart rate were 5.1% (p=0.337), 18.5% (p=0.018) and 1.7%. No significant differences between the treatments were seen for other adverse events.ConclusionsLevosimendan did not achieve the primary endpoint of improving sitting SVC in ALS. Headache and increased heart rate were increased on levosimendan, although it was otherwise well tolerated. A phase III study to evaluate the longer term effects of oral levosimendan in ALS is ongoing.

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.

Nilotinib 300 Mg Twice Daily as First Line Treatment of Ph-Positive Chronic Myeloid Leukemia In Chronic Phase: Updated Results of the ICORG 0802 Phase 2 Study with Analysis of the GeneXpert System Versus IS BCR-ABL RQ PCR.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3427-3427 ◽  
Author(s):  
Eibhlin Conneally ◽  
Ronan T Swords ◽  
Francis J. Giles ◽  
Mary Frances McMullin ◽  
Philipp le Coutre ◽  
...  
Keyword(s):  
Phase Ii ◽  
Chronic Phase ◽  
Phase Iii ◽  
Molecular Response ◽  
Open Label ◽  
Paired Samples ◽  
Oncology Research ◽  
Early Results ◽  
Grade Iii

Abstract Abstract 3427 Recently, early results of the ENESTnd phase III trial showing superiority of nilotinib over imatinib, led to accelerated approval of Nilotinib as initial treatment of ECP CML at a dose of 300mg BID. Independently, since December 2008, ICORG, the All-Ireland Cooperative Oncology Research Group has been conducting an open-label, single stage, multicenter, phase II study (ClinicalTrials.gov NCT00809211) to investigate the safety and efficacy of nilotinib 300 mg BID in untreated, ECP, Ph-pos CML patients. The primary endpoint is the CCyR rate at 6 months; secondary endpoints include the kinetics of molecular response, determined by RQ-PCR at baseline and 3 monthly from start of treatment as well as an evaluation of a new rapid turnaround PCR system “GeneXpert” with IS BCR-ABL RQ-PCR. To date a total of 37 patients have been enrolled on the trial. The median age of these 37 patients is 51 (range 20 –77); 50% have low risk Sokal score, 22% intermediate and 28% high risk. Median follow up is currently 8 months (range 1–17) with 25 patients evaluable for response following at least 3 months on study. Results: By intent to treat analysis the CCyR rate is 64% (16/25) at 3 months and 95% (19/20) at 6 months, with all patients actually tested Ph negative by 6 months. By 6 months 12/20 patients have achieved MMR (60%). This analysis includes 1 patient with variant transcripts and 2 patients bordering on MMR at 3 months who had insufficient RNA for analysis at 6 months. While none of the patients have progressed on study, three patients are now off the study: persistent grade 3 thrombocytopenia in one, persistent LFTS abnormalities in a second case and one death due to progressive multiple system atrophy, which was unrelated. 3 of 25 patients (12%) have undergone dose escalation to 400mg BID for suboptimal response. The median daily dose was 600mg; 16/34 (47%) have interrupted nilotinib at least once with a median duration of interruption of 0.5 days. The dose of nilotinib at the last visit was > 300mg BID in 82% (28/34). Haematologic toxicity was minimal with grade III thrombocytopenia seen in 2 patients (5%). Grade III non-haematologic toxicity included an elevated lipase in 6/36 (17%). The only other grade III toxicities noted were musculo-skeletal pain and an elevated ALT in 1 patient each. Analysis of 71 follow-up paired samples from 21pts at 3 monthly intervals by “GeneXpert” and RQ-PCR showed an encouraging correlation between the methodologies. At 3 months the median BCR-ABL/ABL % was 0.45 as calculated by “GeneXpert” and 0.67 by IS RQ-PCR and at 6 months 0.06 and 0.01 respectively. However in individual patients, there was a trend for “GeneXpert” to underestimate Bcr-Abl/Abl % and therefore overestimate attainment of MMR. Conclusion: In this preliminary analysis, nilotinib 300mg BID induces high rates of CCyR and MMR equivalent to those reported previously in the phase II and III studies of nilotinib in ECP CML. This trial provides independent confirmation that nilotinib 300mg BID is safe and effective treatment for ECP CML. “GeneXpert” provides rapid results both at diagnosis and follow–up and would be further enhanced by calculation of a conversion factor to the IS scale. Disclosures: Conneally: Novartis: Honoraria. Giles:Novartis: Consultancy, Honoraria. Egan:Novartis: Employment. O'Dwyer:Novartis: Honoraria.

Phase II study combining personalized dendritic cell (DC)-based therapy, AGS-003, with sunitinib in metastatic renal cell carcinoma (mRCC).

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 348-348 ◽  
Author(s):  
Robert A. Figlin ◽  
Asim Amin ◽  
Arkadiusz Dudek ◽  
Theodore Logan ◽  
Raymond S. Lance ◽  
...  
Keyword(s):  
Risk Factors ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Single Agent ◽  
Progression Free Survival ◽  
Intradermal Injection ◽  
Phase Iii ◽  
Intermediate Risk ◽  
Open Label ◽  
Poor Risk

348 Background: AGS-003 is a personalized immunotherapy that employs autologous DCs co-electroporated with the subject’s amplified tumor mRNA and synthetic CD40L RNA. Based on previous results with single agent AGS‐003 and acceptance of TKIs as the standard of care for mRCC, AGS-003 was evaluated in combination with sunitinib as initial treatment for advanced RCC. Progression free survival (PFS) results for the combination have been previously presented and show improvement compared to historical data in unfavorable risk patients treated with sunitinib alone. Methods: AGS-003-006 is an open label phase II study that included subjects with newly diagnosed, metastatic clear cell RCC. Tumor was harvested by nephrectomy or metastasectomy for mRNA. Autologous monocytes were collected by leukapheresis for the production of DCs. Subjects subsequently received sunitinib (4wks on, 2wks off) combined with AGS-003 (every 3wks X 5 doses, then every 12wks) until progression. AGS-003 doses consisted of 1 X 107 cells administered by intradermal injection to a single lymph node basin. Response was evaluated per RECIST and subjects followed for PFS and OS. Immune responses were assessed at baseline and after five AGS-003 doses using multiparametric flow cytometry. Results: 25 subjects were enrolled; 21 received treatment. The median PFS from registration for subjects receiving at least one dose of AGS-003 was 11.9 months. For subjects with 1–2 MSKCC risk factors (intermediate risk), PFS = 14.9 months and for subjects with 3–4 MSKCC risk factors (poor risk), PFS = 6.0 months. Median OS from registration has not been reached. Median OS for poor risk subjects = 7.9 months. Median OS for intermediate risk subjects has yet to be reached, but will exceed 28.3+ months. Conclusions: AGS-003 is well tolerated with no immunotherapy-related SAEs or grade 3/4 AEs reported. Interim data indicate that AGS-003 in combination with sunitinib yields a median OS higher than that reported for sunitinib alone in unfavorable risk subjects. Updated OS and immune response correlates will be presented. These results support the ongoing, randomized phase III ADAPT study.

Phase II Study of the Mammalian Target of Rapamycin Inhibitor Ridaforolimus in Patients With Advanced Bone and Soft Tissue Sarcomas

2012 ◽  
Vol 30 (1) ◽  
pp. 78-84 ◽  
Author(s):  
Sant P. Chawla ◽  
Arthur P. Staddon ◽  
Laurence H. Baker ◽  
Scott M. Schuetze ◽  
Anthony W. Tolcher ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Phase Ii ◽  
Single Agent ◽  
Mammalian Target Of Rapamycin ◽  
Soft Tissue Sarcomas ◽  
Phase Iii ◽  
Target Of Rapamycin ◽  
Mucosal Inflammation ◽  
Spindle Cell Sarcoma ◽  
Open Label

PurposeRidaforolimus is an inhibitor of mammalian target of rapamycin, an integral component of the phosphatidyl 3-kinase/AKT signaling pathway, with early evidence of activity in sarcomas. This multicenter, open-label, single-arm, phase II trial was conducted to assess the antitumor activity of ridaforolimus in patients with distinct subtypes of advanced sarcomas.Patients and MethodsPatients with metastatic or unresectable soft tissue or bone sarcomas received ridaforolimus 12.5 mg administered as a 30-minute intravenous infusion once daily for 5 days every 2 weeks. The primary end point was clinical benefit response (CBR) rate (complete response or partial response [PR] or stable disease ≥ 16 weeks). Safety, progression-free survival (PFS), overall survival (OS), time to progression, and duration of response were also evaluated.ResultsA total of 212 patients were treated in four separate histologic cohorts. In this heavily pretreated population, 61 patients (28.8%) achieved CBR. Median PFS was 15.3 weeks; median OS was 40 weeks. Response Evaluation Criteria in Solid Tumors (RECIST) confirmed response rate was 1.9%, with four patients achieving confirmed PR (two with osteosarcoma, one with spindle cell sarcoma, and one with malignant fibrous histiocytoma). Archival tumor protein markers analyzed were not correlated with CBR. Related adverse events were generally mild or moderate and consisted primarily of stomatitis, mucosal inflammation, mouth ulceration, rash, and fatigue.ConclusionSingle-agent ridaforolimus in patients with advanced and pretreated sarcomas led to PFS results that compare favorably with historical metrics. A phase III trial based on these data will further define ridaforolimus activity in sarcomas.

Durable Responses in Patients Treated with Galiximab (Anti-CD80) in Combination with Rituximab for Relapsed or Refractory Follicular Lymphoma: Long-Term Follow-up of a Phase II Clinical Trial.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1004-1004 ◽  
Author(s):  
Jonathan W. Friedberg ◽  
Anas Younes ◽  
David C. Fisher ◽  
Leo I. Gordon ◽  
Joseph O. Moore ◽  
...  
Keyword(s):  
Phase Ii ◽  
Single Agent ◽  
Costimulatory Molecule ◽  
Phase Iii ◽  
Variable Regions ◽  
Long Term Follow Up ◽  
Chi Square Analysis ◽  
Lymphoma Therapy

Abstract Galiximab is an anti-CD80 monoclonal antibody with human IgG1 constant regions and macaque variable regions. CD80 is an immune costimulatory molecule that is constitutively expressed on the surface of follicular lymphomas. Modest single-agent clinical activity (ORR 11%) was demonstrated in a single agent Phase I study of galiximab in relapsed/refractory, follicular NHL with the observation of late and prolonged responses. We previously conducted a phase II multicenter study evaluating the combination of galiximab and rituximab for relapsed/refractory follicular NHL, and demonstrated an ORR of 64% (17% CR, 14% CRu, and 33% PR). Here, we analyze long-term safety and efficacy data from this trial. Patients received galiximab (500 mg/m2 qwk x 4 weeks) concurrently with a standard course of rituximab (375 mg/m2 qwk x 4 weeks). No maintenance therapy was allowed. Sixty-four patients received treatment. Mean age at study entry was 59 yrs. The majority of patients (88%) were Stage III/IV, and FLIPI risk groups were distributed as low (27%), intermediate (39%), and high (34%). All patients had received at least 1 prior lymphoma therapy; 42% were rituximab naïve; rituximab-refractory patients (no response or a response with TTP<6 months) were excluded. The median follow-up of responding patients is 45 months (range 9–59 months). The median PFS was 12.2 months. 20% of patients had PFS durations exceeding 2 years. 37% of patients did not require any additional lymphoma therapy for at least 2 years following treatment (TTNT); 28% had a TTNT of more than 3 years. Grade, tumor bulk, age, stage, prior rituximab exposure, and FLIPI score did not predict for PFS duration of > 2 years, or TTNT duration of > 2 years (p=NS, chi-square analysis). Obtaining a CR predicted for PFS and TTNT duration >2 years (p=0.001). Response duration to prior therapy was not correlated to outcome following rituximab/galiximab therapy (p=0.18). Quantitative immunoglobulin levels (IgA, IgM and IgG) did not differ between prolonged responders and other patients, and did not significantly change over the first year of follow-up. Median Cmax, half-life, AUC and Cl were similar between prolonged responders and other patients. No late opportunistic infections, secondary malignancies, or infusion-associated deaths have been reported. We conclude that the combination of rituximab and galiximab is well-tolerated in long-term follow-up, with a substantial number of durable responses. Almost one-third of patients treated with only 4 weeks of this combination do not require additional lymphoma therapy for more than three years. There is no clear prognostic marker that predicts for prolonged benefit from the combination. These durable responses provide strong rationale for ongoing phase III clinical trials of the galiximab/rituximab combination.

Safety and Tolerability of Obinutuzumab (GA101) with Shorter Duration of Infusion in Japanese Patients with Previously Untreated CD20-Positive B-Cell Non-Hodgkin's Lymphoma (NHL)-Comparison with GAO4915g (GATHER) and BO21005 (GOYA) Studies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5389-5389 ◽  
Author(s):  
Hideki Tsujimura ◽  
Kyoya Kumagai ◽  
Takanori Teshima ◽  
Kiyohiko Hatake ◽  
Koji Izutsu ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Safety Profile ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Phase Iii ◽  
Study Phase ◽  
Type I ◽  
Open Label ◽  
Anti Cd20

Abstract Background Obinutuzumab (GA101) is a novel humanized, glycoengineered Type II anti-CD20 monoclonal antibody. It has greater direct cell death induction and antibody-dependent cell-mediated cytotoxicity and lower complement-dependent cytotoxicity than Type I anti-CD20 antibody rituximab. Studies of obinutuzumab in patients (pts) with previously untreated or relapsed/refractory NHL demonstrated clinical activity with an acceptable safety profile. Infusion-related reactions (IRRs) were the most common adverse event, typically associated with the first infusion. Obinutuzumab 1000 mg is being administered over 4 hrs 15 min for the first infusion on Cycle 1 Day 1, and over 3 hrs 15 min for subsequent infusions. Shortening administration times can result in greater patient convenience and more efficient use of infusion facilities. To evaluate the tolerability of a Shorter Duration of Infusion (SDI), we conducted a Phase II study (JO29737, JapicCTI-152848, 'GATS') of G-CHOP (obinutuzumab in combination with CHOP [cyclophosphamide, doxorubicin, vincristine, prednisolone]) in Japanese pts with previously untreated CD20-positive B-cell NHL. Methods This study included adult pts with previously untreated CD20-positive B-cell NHL. Treatment consisted of 8 cycles of obinutuzumab (1000 mg intravenously on Day 1 of each 21-day cycle, with additional doses on Days 8 and 15 of Cycle 1) plus standard CHOP on Day 1 of Cycles 1-6. Obinutuzumab SDI is administered over 1 hr 30 min. Obinutuzumab was administered as an SDI from Cycle 2 to pts who met the following criteria: (1) No ≥ Gr 3 IRR related to obinutuzumab during regular infusions (RI) in Cycle 1, and (2) Lymphocyte count ≤ 5000/µL in peripheral blood prior to SDI. Primary endpoints were tolerability of SDI, pharmacokinetics (PK) of obinutuzumab. Tolerability of SDI was assessed by incidence of ≥ Gr 3 IRR in Cycle 2. Secondary endpoints were overall safety profile and efficacy. IRRs were defined as AEs related to obinutuzumab occurring during infusion or within 24 hrs from the end of infusion. Results were compared to the multicenter, open-label, randomized GOYA study (phase III, RI G-CHOP), and the multicenter, open-label, single-arm GATHER study (phase II, SDI G-CHOP). The GOYA study included 111 Japanese pts. Results At database lock date, 35 pts were enrolled and treated, including 19 diffuse large B-cell lymphoma, 13 follicular lymphoma, and 3 other histologies; median age was 66 yrs (range, 35-78); 12/35 female; Ann Arbor stage I 11.4%, II 25.7%, III 20.0%, IV 42.9%; 7/35 positive bone marrow involvement. In 7 pts, treatment was prematurely discontinued due to AE (n=3; infected dermal cyst, bronchiolitis, and pneumonia　aspiration, 1 pt each), progressive disease (n=2), or physician's decision (n=2). Thirty-three pts received at least one SDI of obinutuzumab, given in Cycle 2 and subsequent cycles in 31 pts. Overall, 48.6% of pts (17/35) experienced IRRs. They were Gr 1/2 in all cases and occurred most commonly on Day 1 Cycle 1 (RI). No SDI-associated IRR was observed in Cycle 2, and very rare cases (2 pts) were noted in Cycles 6, 7, and 8. IRRs occurring in ≥5% pts were pyrexia (25.7%), chills (8.6%), and nausea, blood pressure increased, and headache (5.7%). Gr ≥3 AEs observed in ≥10% of pts were neutropenia (40.0%), neutrophil count decreased (25.7%), febrile neutropenia (17.1%), and leukopenia (14.3%). Obinutuzumab concentration just after Cycle 2 SDI was the same level as the concentration in Cycle 8. This shows PK reached a steady state at Cycle 2 and was not affected by shortening of administration. From PK analysis in the GATS study, AUC7day was 4170±885 µg·day/mL and t1/2 was 15.4±7.0 day, similar to the GATHER values (AUC7day, 3300±1130 µg·day/mL; t1/2, 23.0±15.9 day) after considering individual variability. No ethnic difference was observed. Overall response rate was 82.9% (29/35) (CR 62.9% [22/35], PR 20.0% [7/35]); 2 pts were not evaluable for response. Conclusions Obinutuzumab can be safely administered as SDI. No SDI-associated IRR was observed in Cycle 2. A few IRRs were observed with SDI in later cycles, but all were tolerable and manageable. RI and SDI have comparable safety, PK, and efficacy profiles in Japanese and non-Japanese. Disclosures Hatake: Meiji-Seika: Consultancy; Kyowa Kirin: Honoraria, Research Funding; Otsuka: Consultancy; Chugai: Research Funding. Izutsu:Abbvie: Research Funding; Gilead: Research Funding; Celgene: Research Funding; Janssen Pharmaceutical K.K.: Honoraria; Eisai: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria; Mundipharma KK: Research Funding. Kinoshita:Janssen: Honoraria; Solasia: Research Funding; Eisai: Honoraria, Research Funding; Ono: Research Funding; Gilead: Research Funding; Kyowa Kirin: Honoraria; Zenyaku: Honoraria, Research Funding; Takeda: Research Funding; Chugai: Honoraria, Research Funding. Tobinai:Kyowa Hakko Kirin: Research Funding; Ono Pharmaceutical: Research Funding; HUYA Bioscience: Honoraria; Chugai Pharma: Research Funding; Eisai: Honoraria, Research Funding; Daiichi Sankyo Co., Ltd.: Consultancy; Celgene: Research Funding; GlaxoSmithKline: Research Funding; Zenyaku Kogyo: Honoraria; SERVIER: Research Funding; Abbvie: Research Funding; Takeda: Honoraria, Research Funding; Mundipharma KK: Honoraria, Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding.

Open-label study of pemetrexed alone for chemonaive patients and pre-treated patients with malignant pleural mesothelioma: Outcomes of the International Expanded Access Program (EAP)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7709-7709
Author(s):  
P. Taylor ◽  
J. von Pawel ◽  
B. Castagneto ◽  
G. Dark ◽  
M. Marangolo ◽  
...  
Keyword(s):  
Median Survival ◽  
Phase Ii ◽  
Malignant Pleural Mesothelioma ◽  
Survival Data ◽  
Single Agent ◽  
Safety Data ◽  
Phase Iii ◽  
Pleural Mesothelioma ◽  
Open Label ◽  
Pretreated Group

7709 Background: In a previous phase II study of chemonaive malignant pleural mesothelioma (MPM) patients (pts), single-agent pemetrexed (P) resulted in a 14.1% response rate (RR) and median survival of 10.7 mos (95% CI 7.7–14.5) (Scagliotti 2003). Likewise, the P arm in a phase III study of pre-treated MPM pts yielded an 18.7% RR (40.7% with stable disease, SD) and median survival of 8.4 mos (95% CI 6.2–10.5) (Jassem 2006). The EAP provided 3311 MPM pts with access to P alone, P plus cisplatin, or P plus carboplatin in 13 countries. In this abstract we report on the safety and efficacy data of those MPM pts treated with P alone. Methods: Eligible pts had histologic or cytologic diagnosis of MPM and were either chemonaïve or previously treated with =1 line(s) of chemotherapy. Pts pre-treated with P were allowed if they had experienced clinical benefit from the prior P. Treatment consisted of P (500 mg/m2) once (day 1) every 21 days with standard pre-medication of vitamin B12, folic acid, and dexamethasone. Investigator-determined response (RR) and survival data (with censoring) were recorded at the end of study participation. Myelosuppression data (CTC) were also collected. Results: 812 MPM pts (319 chemonaïve; 493 pre-treated) received =1 dose of P and were evaluated for safety, and 643 pts (247 chemonaïve; 396 pre-treated) were evaluated for efficacy (RR and survival). In chemonaïve pts with MPM, the median age was 69 yrs (range: 39–87 yrs), 78.1% were male, and 71.6% had a KPS ≥80 (of the 93% who had PS evaluated). In pre-treated pts with MPM, the median age was 63 yrs (range: 31–85 yrs), 75.9% were male, and 74.5% had a KPS ≥80 (of the 95% who had PS evaluated). Both groups received a median of 4 cycles (chemonaive group range 1–18; pretreated group range 1–23). See the table for efficacy and safety data. Conclusions: Results of the EAP confirm earlier phase II and phase III studies. No significant financial relationships to disclose. [Table: see text]

Phase II study of the IDH2-inhibitor enasidenib in patients with high-risk IDH2-mutated myelodysplastic syndromes (MDS).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7010-7010
Author(s):  
Sangeetha Venugopal ◽  
Courtney Denton Dinardo ◽  
Koichi Takahashi ◽  
Marina Konopleva ◽  
Sanam Loghavi ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Single Agent ◽  
Median Number ◽  
International Prognostic Scoring System ◽  
Open Label ◽  
Isocitrate Dehydrogenase 2 ◽  
Treatment Naïve ◽  
Grade 3

7010 Background: Isocitrate dehydrogenase 2 ( IDH2) mutations occur in 5% of patients (pts) with MDS. Enasidenib (ENA) is a selective oral inhibitor of the mutant IDH2 enzyme with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We report the results of the open label phase II study designed to evaluate the efficacy and tolerability of ENA, as monotherapy or in combination with azacitidine (AZA) in pts with higher-risk IDH2-mutated MDS (NCT03383575). Methods: Pts with higher-risk [Revised International Prognostic Scoring System risk > 3 or high molecular risk (HMR)] MDS/CMML or LB AML naïve to hypomethylating agents (HMA) received ENA100 mg orally daily for 28 d of each 28-d cycle + AZA 75 mg/m2 IV or SC on d 1-7 of each cycle (ENA+AZA), and pts with refractory or progressive MDS to prior HMA therapy received ENA alone (ENA), in 28-d cycles until unacceptable toxicity, relapse, transformation to AML, or progression. The primary endpoint was overall response rate (ORR) [complete remission (CR), marrow CR (mCR), partial remission (PR) and hematologic improvement (HI)]. Other endpoints include safety, and survival outcomes. Results: 48 pts received ENA+AZA (n = 26) or ENA (n = 22). The median age was 73 yrs (range, 46-83). Most pts (72%) had HMR: ASXL1 (39%), and RUNX1 (17%). Median number Tx cycles was 4 (2–32) in the ENA+AZA, and 7 (1–23) in the ENA arm. Common Tx-related grade 3–4 AEs in the ENA+AZA arm were neutropenia (64%), thrombocytopenia (28%), and anemia (8%); these occurred in 10%, 0%, and 5%, in the ENA arm. Grade 3–4 infections occurred in 32% (ENA+AZA) and 14% (ENA). IDH differentiation syndrome occurred in 3 pts (12%) in the ENA+AZA and 5 pts (24%) in the ENA arm. Two deaths occurred during the initial 60 d, both unrelated to study and due to COVID. In response-evaluable pts (n=46), ORR was 84% (n = 21/25; 24% CR + 8% PR+44% mCR+ 8% HI] in the treatment naïve ENA+AZA and 43% (n = 9/21; 24% CR+5%PR+5% mCR+10% HI) in the HMA failure ENA arm (Table). Most common reason for Tx discontinuation was disease progression (ENA+AZA 20%, ENA 33%).5 pts (20%) received HCT in the ENA+AZA and 1 (5%) in the ENA arm. 7 pts in the ENA+AZA and 5 in the ENA arm were ongoing at data cutoff (Dec 31, 2020). After a median follow up of 12.6 mo, median OS was 32.2 mo in the ENA+AZA and 21.3 mo in the ENA arm. Conclusions: ENA is well tolerated and shows promising efficacy in IDH2-mutated higher risk MDS. Follow up and accrual is ongoing to better define duration and biomarkers of response. Clinical trial information: NCT03383575. [Table: see text]

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