Updated 5-y landmark analyses of phase 2 (BREAK-2) and phase 3 (BREAK-3) studies evaluating dabrafenib monotherapy in patients with BRAF V600–mutant melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9526-9526 ◽  
Author(s):  
Paul B. Chapman ◽  
Paolo Antonio Ascierto ◽  
Dirk Schadendorf ◽  
Jean Jacques Grob ◽  
Antoni Ribas ◽  
...  
Keyword(s):  
Single Agent ◽  
Braf Inhibitor ◽  
Stage Iv ◽  
Braf V600e ◽  
Phase 2 ◽  
Open Label ◽  
Phase 3 ◽  
Study Results ◽  
Landmark Analyses

9526 Background: Prior analyses of phase 2 (BREAK-2; NCT01153763) and phase 3 (BREAK-3; NCT01227889) trials showed that durable clinical benefit and tolerability lasting ≥ 3 y are achievable with the BRAF inhibitor dabrafenib in some patients (pts) with BRAFV600–mutant metastatic melanoma. Here, we report 5-y landmark analyses for BREAK-2 and BREAK-3. Methods: BREAK-2, a single-arm, phase 2 study, evaluated dabrafenib 150 mg twice daily in pts with stage IV BRAF V600E/K–mutant MM. BREAK-3, an open-label, randomized (3:1), phase 3 study, assessed dabrafenib 150 mg twice daily vs dacarbazine 1000 mg/m2 every 3 weeks in pts with previously untreated BRAFV600E–mutant unresectable stage III or stage IV MM. Updated analyses were performed to describe ≥ 5-y outcomes in each study. Results: BREAK-2 enrolled 92 pts (V600E, n = 76; V600K, n = 16), of whom most (90%) had prior systemic anticancer therapy. At data cutoff (17 Jun 2016), all pts had discontinued, mostly due to progression (84%). In V600E pts, 5-y progression-free survival (PFS) was 11%, and 5-y overall survival (OS) was 20%. Postprogression immunotherapy was received by 22% of enrolled pts. In BREAK-3 (data cutoff, 16 Sep 2016), median follow-up was 18.6 mo for the dabrafenib arm (n = 187) and 12.8 mo for the dacarbazine arm (n = 63). Follow-up for the 37 dacarbazine-arm pts (59%) who crossed over to receive dabrafenib was based on the initial assignment of dacarbazine. The 5-y PFS was 12% vs 3% and 5-y OS was 24% vs 22% for the dabrafenib and dacarbazine arms, respectively. A subset of pts in each respective arm received postprogression anti–CTLA-4 (24% vs 24%) and/or anti–PD-1 (8% vs 2%) therapy, whereas 31% vs 17% did not receive any further therapy following study treatment. No new safety signals were observed in either study with long-term follow-up. Additional characterization of pts using cfDNA analysis will be presented. Conclusions: These data provide the longest reported PFS and OS follow-up for BRAF inhibitor monotherapy in BRAF V600–mutant MM. Both BREAK-2 and BREAK-3 showed that 11%-12% of pts initially treated with single-agent dabrafenib remained progression free at 5 y. Clinical trial information: NCT01153763; NCT01227889.

scholarly journals Treatment of early-stage breast cancer with percutaneous thermal ablation, an open-label randomised phase 2 screening trial: rationale and design of the THERMAC trial

BMJ Open ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. e052992
Author(s):  
Elles M F van de Voort ◽  
Gerson M Struik ◽  
Linetta B Koppert ◽  
Adriaan Moelker ◽  
Reno Debets ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Thermal Ablation ◽  
Surgical Excision ◽  
Maximum Diameter ◽  
Phase 2 ◽  
Open Label ◽  
Phase 3 ◽  
Complete Ablation ◽  
Study Results ◽  
Screening Trial

IntroductionBreast cancer is the most frequently diagnosed malignancy worldwide but almost half of the patients have an excellent prognosis with a 5-year survival rate of 98%–99%. These patients could potentially be treated with thermal ablation to avoid surgical excision, reduce treatment-related morbidity and increase patients’ quality of life without jeopardising treatment effectiveness. Previous studies showed highest complete ablation rates for radiofrequency, microwave and cryoablation. However, due to heterogeneity among studies, it is unknown which of these three techniques should be selected for a phase 3 comparative study.Methods and analysisThe aim of this phase 2 screening trial is to determine the efficacy rate of radiofrequency, microwave and cryoablation with the intention to select one treatment for further testing in a phase 3 trial. Additionally, exploratory data are obtained for the phase 3 trial. The design is a multicentre open-label randomised phase 2 screening trial. Patients with unifocal, invasive breast cancer with a maximum diameter of 2 cm without lymph node or distant metastases are included. Triple negative, Bloom-Richardson grade 3 tumours and patients with an indication for neoadjuvant chemotherapy will be excluded. Included patients will be allocated to receive one of the three thermal ablation techniques. Three months later surgical excision will be performed to determine the efficacy of thermal ablation. Treatment efficacy in terms of complete ablation rate will be assessed with CK 8/18 and H&E staining. Secondary outcomes include feasibility of the techniques in an outpatient setting, accuracy of MRI for complete ablation, patient satisfaction, adverse events, side effects, cosmetic outcome, system usability and immune response.Ethics and disseminationThis study protocol was approved by Medical Research Ethics Committee of the Erasmus Medical Center, Rotterdam, the Netherlands. Study results will be submitted for publication in peer-reviewed journals.Trial registration numberNL9205 (www.trialregister.nl); Pre-results.

BREAKWATER: Randomized phase 3 study of encorafenib (enco) + cetuximab (cetux) ± chemotherapy for first-line (1L) treatment (tx) of BRAF V600E-mutant (BRAFV600E) metastatic colorectal cancer (mCRC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3619-TPS3619
Author(s):  
Scott Kopetz ◽  
Axel Grothey ◽  
Rona Yaeger ◽  
Fortunato Ciardiello ◽  
Jayesh Desai ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Objective Response ◽  
Braf Inhibitor ◽  
Braf V600e ◽  
Egfr Inhibitor ◽  
Braf Mutations ◽  
Open Label ◽  
Phase 3 ◽  
Previously Treated

TPS3619 Background: Approximately 10% of patients (pts) with mCRC have BRAF mutations (mostly V600E). 1L tx options for BRAFV600E mCRC are limited to cytotoxic chemotherapy ± anti-VEGF or anti-EGFR, or immune checkpoint inhibitors in pts with MSI-H tumors. In Europe, Japan, and USA, the combination of BRAF inhibitor enco + EGFR inhibitor cetux is approved for tx of BRAFV600E mCRC after prior therapy. In BEACON CRC, enco + cetux resulted in a median overall survival (OS) of 9.3 months (95% confidence interval [CI]: 8.0–11.3) and an objective response rate (ORR) of 19.5% (95% CI: 14.5%–25.4%) in previously treated pts with BRAFV600E mCRC (median follow-up: 12.8 months); 57.4% of pts had grade 3/4 adverse events (AEs); 9% discontinued due to AEs. Given the poor prognosis of pts with BRAFV600E mCRC and based on the efficacy and tolerability of enco + cetux from BEACON CRC, BREAKWATER will evaluate efficacy and safety of enco + cetux ± chemotherapy in tx-naive pts with BRAFV600E mCRC. Methods: BREAKWATER is an open-label, global, multicenter, randomized, phase 3 study with a safety lead-in (SLI). Approximately 60 and 870 pts will be enrolled in the SLI and phase 3 parts of the study, respectively. Pts must have BRAFV600E mCRC (determined using tumor tissue or blood); ECOG performance status 0/1; and adequate bone marrow, hepatic, and renal function. Pts in the SLI must have evaluable disease (RECIST v1.1) and have received ≤ 1 prior tx regimen; those previously treated with a BRAF or EGFR inhibitor, or both oxaliplatin and irinotecan, will be excluded. Pts in the phase 3 study must have measurable disease and be tx naive for metastatic disease. Study tx and endpoints are shown in the table. Enrollment began on 6 January 2021. Clinical trial information: NCT04607421. [Table: see text]

scholarly journals Apatinib plus camrelizumab (anti-PD1 therapy, SHR-1210) for advanced osteosarcoma (APFAO) progressing after chemotherapy: a single-arm, open-label, phase 2 trial

2020 ◽  
Vol 8 (1) ◽  
pp. e000798
Author(s):  
Lu Xie ◽  
Jie Xu ◽  
Xin Sun ◽  
Wei Guo ◽  
Jin Gu ◽  
...  
Keyword(s):  
Pulmonary Metastases ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Open Label ◽  
Phase 2 Trial ◽  
Open Label Phase ◽  
High Grade Osteosarcoma

BackgroundResults of our previous study showed high objective response but short-term activity of apatinib in advanced osteosarcoma. We aimed to investigate the activity of apatinib in combination with camrelizumab in patients with inoperable high-grade osteosarcoma progressing after chemotherapy.MethodsThis open-label, phase 2 trial was conducted at Peking University People’s Hospital. We enrolled patients with advanced osteosarcoma progressed after chemotherapy. Patients received 500 mg apatinib orally once daily plus 200 mg camrelizumab by intravenous infusion every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) and clinical benefit rate at 6 months, which were based on RECIST V.1.1.Results43 patients were enrolled between January 25 and September 4, 2018. With median follow-up time of 48.3 (Q1, Q3, 30.6, 66.6) weeks, 13 (30.23%, 95% CI 17.2%, 40.1%) of 43 patients were progression free at 6 months and the 6-month PFS rate was 50.9% (95% CI 34.6%, 65.0%). Until final follow-up, the objective response rate was 20.9% (9/43) and two patients with durable disease control were observed. Patients with programmed cell death 1 ligand-1 (PD-L1) tumor proportion score ≥5% and pulmonary metastases tended to have a longer PFS in comparison to the others (p=0.004 and 0.017, respectively). Toxic effects led to dose reductions, or interruptions, or both in 24 (55.8%) of 43 patients and permanent discontinuation in 4 (9.3%) patients. There were no treatment-related deaths.ConclusionsAlthough the combination of apatinib and camrelizumab seemed to prolong PFS in comparison to single agent apatinib in treating advanced osteosarcoma, it did not reach the prespecified target of 6-month PFS of 60% or greater. Overexpression of PD-L1 and the presence of pulmonary metastases only were associated with longer PFS.Trial registration numberNCT03359018.

Phase 2 trial of talabostat and cisplatin in patients with stage IV melanoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8040-8040 ◽  
Author(s):  
C. Cunningham ◽  
A. C. Pavlick ◽  
K. D. Khan ◽  
G. Frenette ◽  
S. O’Day ◽  
...  
Keyword(s):  
T Cell ◽  
Organ Failure ◽  
Oral Delivery ◽  
Single Agent ◽  
Stage Iv ◽  
Phase 2 ◽  
Open Label ◽  
Eligibility Criteria ◽  
Cell Immunity ◽  
Stage Iv Melanoma

8040 Background: Talabostat (TAL) is an oral inhibitor of dipeptidyl peptidases such as fibroblast activation protein found on the stroma of tumors, draining lymph nodes, and in melanomas. TAL up-regulates cytokines and chemokines, leading to specific T-cell immunity and T-cell independent activity. TAL significantly enhances the activity of cisplatin (C) in mice, and reduces tumor size >60% in melanoma xenografts (A375, A2058). This trial evaluated the activity of TAL and C in patients with Stage IV melanoma. Methods: Open-label, single-arm, Phase 2 study of 4 x 3-week cycles of C-75mg/m2 (Day 1) and TAL-300mcg BID orally on Days 2–15 with dose-escalation to TAL-400mcg BID depending on tolerability. Single-agent TAL could be continued beyond 4 cycles until disease progression or unacceptable toxicity. Eligibility criteria included: ≤1 prior bio- or chemotherapy regimen, ECOG 0–2, measureable disease per RECIST, no symptomatic CNS metastases, LDH, ALT, and AST <3X ULN. Primary endpoint was disease response; secondary endpoints included PFS, duration of response, and survival. Results: 74 patients (50 men, 24 women) entered the study; median age was 58 years (range 27 to 79); 94.6% were caucasian. Most patients (71.4%) were M1c, and the majority (64.3%) had received at least 1 prior regimen; 72.9% of these had received prior cytokine treatment. A PR was reported in 5/42 evaluable patients (11.9%), and SD for at least 4 cycles in an additional 21/42 (50%). Median PFS and survival are currently estimated at 2.6 months (95% CI 2.1, 3.4) and 8.5 months (95% CI 5.4, infinity), respectively in the ITT population. Most frequent AEs were nausea (46%), fatigue (35%), and vomiting (34%); the high unevaluability rate patients was due to non-compliance related to C-associated N/V (thus the dose of C was reduced mid-study from 100 to 75mg/m2). Grade 3 toxicities were neutropenia, fatigue, and dehydration, all at 3.4%. Grade 4 toxicities were organ failure, renal failure, and PD (1 patient each). 4 patients died due to PD, and 1 each due to renal and organ failure. Conclusions: The combination of TAL and C is active in patients with Stage IV melanoma. Most AEs were related to C-associated nausea and vomiting, limiting the oral delivery of TAL. Additional studies of TAL in melanoma with other drug combinations are warranted. [Table: see text]

scholarly journals Dabrafenib Is a Safe and Effective Therapy in Relapsed/Refractory Classical Hairy Cell Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-8
Author(s):  
Matthew J Cross ◽  
Paras Shah ◽  
Kara Heelan ◽  
Claire E. Dearden ◽  
Dima El-Sharkawi ◽  
...  
Keyword(s):  
Hairy Cell Leukemia ◽  
Treatment Options ◽  
Single Agent ◽  
Braf Inhibitor ◽  
Skin Lesions ◽  
Braf V600e ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Hematological Response

BACKGROUND: Hairy cell leukemia (HCL) is a rare indolent B-cell lymphoproliferative disorder. The BRAF V600E mutation was shown to be the underlying genetic driver for the vast majority of classical HCL (HCLc) cases and treatment with the BRAF inhibitor (BRAFi), vemurafenib, has proven extremely successful. Dabrafenib is an oral BRAFi used in melanoma, often in conjunction with trametinib, a MEK inhibitor. Data exists on the use of dabrafenib combined with trametinib in HCLc but there is no efficacy or safety data on either single agent dabrafenib or dabrafenib combined with rituximab. We present a small series of 7 patients treated with either single agent dabrafenib or combination dabrafenib and rituximab. METHODS: Since 2018 dabrafenib was accessible via a Novartis managed access programme for BRAF V600E mutated HCLc patients who had no alternative treatment options. Six patients received dabrafenib, 2 as single agent due to recent prior ineffective rituximab therapy or severe rituximab infusion reaction and the remaining 4 patients with dabrafenib and rituximab. Dabrafenib was given at 150mg twice daily on a continuous 28 day cycle. Rituximab 375mg/m2 IV was given once every 2 weeks for a total of 8 doses. As there was no availability for re-treatment on cessation of therapy and no other suitable/accessible treatment options, patients with ongoing response and good tolerance were continued on indefinite therapy. One additional patient was treated with frontline dabrafenib and rituximab due to various comorbidities including end stage renal failure limiting other treatment options. RESULTS: Mean age on commencing dabrafenib was 73 (52-87) and in the relapsed patients the median number of prior lines of therapy was 5 (3-13). Four patients had undergone prior splenectomy. Two patients had received prior BRAFi therapy with vemurafenib and 3 had received prior Moxetumomab. Patients received a median of 8 cycles of dabrafenib. 4 patients received all 8 cycles of rituximab with 1 discontinuing rituximab due to adverse drug reaction. Adverse drug reactions to dabrafenib were mostly grade 1-2. The most common reaction was benign keratotic skin lesions occurring in 5/7 patients. Their onset was typically after 4 weeks of treatment, persisting whilst therapy continued. Other notable adverse drug reactions were hair thinning and palmar-plantar erythrodysesthesia both occurring in 3/7 patients. Hair thinning did seem to improve with decreasing the dosage and resolve on cessation of the drug. Palmar-plantar erythrodysesthesia was managed with dose reduction and non-steroidal anti-inflammatory drugs. Response assessment criteria used were from the 2017 hairy cell leukemia foundation consensus guidelines for the diagnosis and management of patients with HCLc. All patients responded to therapy. Hematological response was rapid, most patients achieving hematological CR after 2-3 cycles. Five patients achieved a CR, 2 were MRD+ve, 2 were MRD-ve and 1 was a radiological CR. The remaining 2 patients achieved a hematological response, 1 partial and 1 complete. Six patients had sufficient follow up for assessment with 2/6 having relapsed and 4/6 remaining in remission. Median follow up was 17 months, median DOR and median OS were not reached. The 2 patients in our cohort (patients 1 and 3) receiving prior vemurafenib each received 6 cycles, 1 achieving CR lasting 3 months, the other achieving PR lasting 11 months. Both responded rapidly to dabrafenib, one treated with dabrafenib and rituximab achieved an MRD+ve CR with DOR 21 months. The other received single agent dabrafenib and achieved a hematological response with DOR 15.2 months. Treatment response and survival are shown in table 1 and figure 1. Figures 2-7 show the hematological response at time points within the first year of therapy. DISCUSSION: In this small cohort we have shown that dabrafenib as a single agent or combined with rituximab is a safe and effective therapy in BRAF V600E mutated HCLc, even in those patients with prior time limited duration BRAFi therapy. There was no hematological toxicity noted. The main adverse drug effect was development of skin lesions however none were malignant. The only malignant lesion noted pre dated the commencement of dabrafenib. Dermatological surveillance is therefore recommended. Hematological response was rapid with significant improvement seen as early as 4 weeks from commencing therapy. Disclosures El-Sharkawi: Janssen:Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche:Other: Conference fees. OffLabel Disclosure: Use of BRAF inhibitor Dabrafenib in BRAF V600E mutation positive classical Hairy Cell Leukemia.

Cabozantinib (CABO) plus durvalumab (DURVA) in patients with advanced and chemotherapy-treated bladder carcinoma of urothelial and non-urothelial histology: An open-label, single-arm, phase 2 trial.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS536-TPS536 ◽  
Author(s):  
Andrea Necchi ◽  
Patrizia Giannatempo ◽  
Daniele Raggi ◽  
Andrea Anichini ◽  
Giuseppina Calareso ◽  
...  
Keyword(s):  
Bone Metastases ◽  
Immune Cell ◽  
Single Agent ◽  
Phase 2 ◽  
Open Label ◽  
Phase 2 Trial ◽  
Effective Combination ◽  
Platinum Based Chemotherapy ◽  
Ecog Ps

TPS536 Background: DURVA and CABO have shown single-agent activity in patients (pts) with urothelial carcinoma (UC). Their combination may result in prolonging overall survival (OS) in pts who have failed prior platinum-based chemotherapy (CT). Additionally, DURVA+CABO may be an effective combination for treating subgroup of pts like those with bone metastases only (not having RECIST-measurable disease) or with non-UC histology. Methods: In an open-label, single-arm, multicenter, phase 2 trial, pts will assume CABO 40 mg daily, orally, and will be administered DURVA 1500 mg, intravenously, q28 days, until disease progression (PD, RECIST 1.1) or onset of unacceptable toxicity. Treatment beyond PD is not allowed. Key inclusion criteria: ECOG-PS 0-1, bladder or upper tract primary tumor, UC and non-UC histology, failure of 1 or 2 platinum-based CT for metastatic disease (2nd-to-3rd line only). Neoadjuvant/adjuvant CT is counted if relapse occurred ≤6 months (m) of the last CT cycle. Response is evaluated by RECIST criteria v.1.1 q2 cycles. The primary endpoint of the study is OS. The target is to detect an improvement in median OS from ≤6m (H0) to ≥9m(H1). To achieve 90% power with a one-sided non-parametric test at 5% significance, 122 pts must will be accrued over 36m and follow-up may be closed 12m after the end of accrual. PD-L1 expression will be assessed using with the Ventana SP142 assay, and categorized as high (≥25% of tumor cells [TC] or immune cells [IC]) or low/negative ( < 25% TC or IC). The decision on whether or not to undertake PD-L1+ cohort expansion will be based on predictive power (PP) calculation: a PP ≥30% will be regarded as promising and necessary to continue. An interim analysis is planned after 24m (50% expected events). This analysis will be based on PP. The criterion for stopping the trial because of futility will be a PP < 20%. Analyses on tissue/blood samples will include immune-cell profiling, cytokine assessment, gene expression analyses and next-generation sequencing (FoundationOne). FDG-PET response in bone metastases will represent another translational endpoint (EudraCT number 2017-000580-32). Clinical trial information: 2017-000580-32.

335 Evaluation of Dose Transition From Zolpidem to Lemborexant Across 14 Weeks: Results From a Multicenter Open-label Pilot Study

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A134-A134
Author(s):  
Russell Rosenberg ◽  
Jess Amchin ◽  
Dinesh Kumar ◽  
Carlos Perdomo ◽  
Norman Atkins ◽  
...  
Keyword(s):  
Pilot Study ◽  
Extended Release ◽  
Open Label ◽  
Phase 3 ◽  
Titration Period ◽  
Study Results ◽  
Dose Change ◽  
Extension Period ◽  
Common Teaes

Abstract Introduction E2006-A001-312 (Study 312; NCT04009577) was an open-label pilot study that examined pre-specified dosing paradigms for transitioning patients from zolpidem (ZOL: immediate [IR] or extended-release [ER]) to the dual orexin receptor antagonist lemborexant (LEM; 5mg [LEM5] or 10mg [LEM10]). Methods Study 312 included a 3-week Screening Period (subjects continued ZOL), 2-week Titration Period (TITR), 12-week Extension Period (EXT), and 4-week Follow-up Period. Adults with insomnia who were intermittent (3–4 nights/week) or frequent (≥5 nights/week) ZOL-IR or ZOL-ER users participated. Intermittent ZOL users and subjects with one week each of intermittent and frequent ZOL usage were assigned to Cohort-1 and began TITR with LEM5. Frequent ZOL users were assigned to Cohort-2 and randomized 1:1 to LEM5 or LEM10. Subjects who successfully transitioned to LEM had the option to enter EXT. During TITR and EXT, subjects could change LEM dose (only once during TITR). The primary endpoint was the proportion of subjects who transitioned to LEM at the end of TITR. Treatment-emergent adverse events (TEAEs) were assessed based on dose at time of TEAE. Results Fifty-three subjects enrolled (Cohort-1, n=10; Cohort-2, n=43). Of these, 43/53 (81.1%) transitioned to LEM at the end of TITR; all 43 (100.0%) entered EXT wherein 41/43 subjects received treatment. Three of these subjects discontinued treatment during EXT, so that 38/41 (92.7%) subjects entered EXT, received treatment and completed EXT. At the end of EXT, 25/41 (61.0%) subjects were receiving LEM10 and 16/41 (39.0%) were receiving LEM5. Based on modal dose (most frequent dose taken during TITR and EXT combined) groups, median time to first dose change was 14.5 days and 36.0 days for LEM5 and LEM10, respectively. The majority of TEAEs were mild/moderate in severity. Across the study (TITR and EXT), more TEAEs occurred with LEM10 than LEM5; the most common TEAEs were somnolence (n=4) and abnormal dreams (n=4). Conclusion Study results support the view that patients can successfully transition directly from ZOL to LEM. LEM was generally well tolerated; the safety profile was consistent with that observed in Phase 3 clinical development. Support (if any) Eisai Inc.

scholarly journals Role of Ibrutinib Based Regimen in Chronic Lymphocytic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5563-5563
Author(s):  
Muhammad Sardar ◽  
Saad Ullah Malik ◽  
Ali Younas Khan ◽  
Chaudhry Saad Sohail ◽  
Malik Qistas Ahmad ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Response Rate ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Cochrane Library ◽  
Combination Regimen ◽  
Phase 2 ◽  
Phase 3 ◽  
Phase 2 Trial

Abstract Background: Treatment of Chronic lymphocytic leukemia (CLL) depends on stage of disease, age, functional status, comorbidities and presence of cytogenetic abnormalities such as (del17p mutation). Ibrutinib was initially approved in CLL given its better response in del17p patients as compared to the standard chemo immunotherapy. Since initial approval, Ibrutinib has also been evaluated in del17p negative CLL patients. Aim of our study is to discuss the efficacy of ibrutinib based regimen in CLL. Methods: Seven databases (Pub Med/Medline, Elsevier/Embase, Elsevier/Scopus, Wiley/Cochrane Library, and Thomas Reuters/Web of Science, EBSCO/CINAHL, and ClinicalTrials.gov.) were searched in accordance with PRISMA statement guidelines using the following keywords: chronic lymphocytic leukemia, CLL, Bruton tyrosine kinase inhibitor, BTK inhibitor, ibrutinib, and PCI32765. Inclusion criteria included prospective clinical trials using Ibrutinib in CLL patients with outcome data available. We excluded systematic reviews, met analysis, case reports and case series. Aim of our review was to evaluate overall response rate (ORR), complete response rate (CR), progression free survival (PFS) and overall survival (OS). Results: Treatment naïve (TN)patientIn the extended 5-year median follow up of a phase 1/2b trial (n=31), the ORR with single agent Ibr was 87% (CR-29%). The 5-year PFS and OS was 92%. In phase 3 trial by Burger et al (2015), ORR with Ibr was 92% (CR18%) in 136 patients. 2-year PFS and OS was 89% and 95% respectively. Del17p patients were excluded. Recent phase 2 trial by Jain et al (2017), combination of ibr with fludarabine (flu), cyclophosphamide (cyclo) and obinutuzumab (G) achieved ORR of 100% (CR 46%) in 32 del17p negative patients. In the phase 2 trial by Davids et al (2017) in 49 patients (< 65 years) the ORR was 100% (CR 63%). Phase 1b/2 trial by Migouel, ORR was 96% (CR 52%) with a combination regimen of Ibr + G + venetoclax. Relapsed/refractory (R/R) patient :In a phase 3 trial by Byrd et al (2014), in 195 patients (median age: 67; del17p: 32%; median prior therapies: 3) the ORR was 63%(CR-O). Median follow up was 9.4 months with 6-month PFS of 88% and 12 months OS of 90%. Phase 2 trial by Burger et al (2014), the ORR was 95% (CR 8%) in 40 patients (median age:63%; del17p:50%; median prior therapies:2). The 18-month PFS and OS was 78% and 84% respectively. In the phase 3 trial by Chanan et al (2016), in 289 (median age 64) del17p negative patients with 2 median prior therapies treated with combination of Ibr + bendamustine + R, the ORR was 83% (CR 10%). The 18-month PFS was 79%. In the phase 3 trial by Sharman et al (2017), in the Ibr + ublituximab arm (n=64) the ORR was 78% (CR 7%) which was higher than in Ibr arm (n= 62) i.e 45% (CR 0). Median age was 67 and each arm received 3 median prior therapies. Del17p was positive in 64% and 66% respectively. Del17p patients: In the phase 2 trial of by Susan et al (2017), in 145 del17p positive patients (median age: 64) treated with Ibr, the ORR was 64% (CR 0). The median prior number of therapies was 2. Patients were followed for a median of 11.5 months and the 2-year PFS and OS was 63% and 75% respectively. Farooqui et al (2014) evaluated Ibr in del17p patients. In 35 TN patients the ORR was 97% (CR -0) with a 2 year PFS and OS of 82% and 84% respectively. In 16 R/R patients, ORR was 80% (CR 0) and the 2 year PFS and OS were 82% and 74% respectively. Median age was 62 Conclusion: Ibrutinib is the treatment of choice for patients with del17p mutation and has good efficacy in RR/TN patients without del17p mutation. Ibrutinib is being evaluated in combination with rituximab for del17p mutations. Future prospects include combination of Ibrutinib with frontline chemotherapy and other novel agents for TN and RR del17p negative patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Vemurafenib Plus Rituximab in Hairy Cell Leukemia: A Promising Chemotherapy-Free Regimen for Relapsed or Refractory Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1214-1214 ◽  
Author(s):  
Enrico Tiacci ◽  
Luca De Carolis ◽  
Francesco Zaja ◽  
Achille Ambrosetti ◽  
Eugenio Lucia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Hairy Cell Leukemia ◽  
Limit Of Detection ◽  
Single Agent ◽  
Braf Inhibitor ◽  
Braf V600e ◽  
Phase 2 ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Purine Analogs

Abstract BACKGROUND: Hairy cell leukemia (HCL) responds well to purine analogs, but up to 50% of patients relapse. We previously identified the BRAF-V600E mutation as the genetic lesion underlying HCL (NEJM 364:230-2315, 2011), and successfully targeted this mutation in the clinic with the oral BRAF inhibitor vemurafenib through an academic phase-2 multi-center Italian trial in HCL patients relapsed after or refractory to purine analogs (NEJM 373:1733-1747, 2015). In these heavily pre-treated patients, vemurafenib given for a median of 16 weeks produced 96% of responses, including 9/26 (35%) complete remissions (CR) and 16/26 (61%) partial remissions (PR), which were obtained after a median of 8 weeks of treatment. Even in complete responders, immunohistochemistry showed residual (~10%) bone marrow HCL cells at the end of treatment, and relapses were common, occurring at a median of 19 months and 6 months in CR and PR patients respectively. Residual HCL cells resisting vemurafenib treatment might be targeted by concomitant immunotherapy with an anti-CD20 monoclonal antibody, an attractive strategy to potentially achieve a more profound response and a better clinical outcome through a chemotherapy-free approach. METHODS: We started an academic, phase-2, single-center trial (EudraCT 2014-003046-27) in relapsed/refractory HCL, which tests vemurafenib in combination with rituximab, another targeted non-myelotoxic drug with known single-agent activity in HCL. Eligibility was extended to patients relapsed also after monotherapy with a BRAF inhibitor. Vemurafenib was given at its standard dose (960 mg twice daily orally) for 8 weeks. Rituximab infusions (375 mg/m2intravenously) were given concomitantly with vemurafenib every 2 weeks, as well as sequentially (after the end of vemurafenib dosing) four times every 2 weeks. RESULTS: We have so far enrolled 22 patients in 16 months. Adverse reactions were reversible, usually mild and consistent with the known toxicity profile of the two drugs when used alone. Notably, a CR was achieved by all 14 patients already evaluable for efficacy (100%), including 4 who had relapsed after a BRAF inhibitor and 1 previously refractory to rituximab. Furthermore, 12/14 patients (86%) obtained the CR as early as after 4 weeks of vemurafenib and 2 concomitant rituximab infusions. This CR rate appears higher than that observed by us and others using vemurafenib alone in BRAF inhibitor-naive patients relapsed after or refractory to purine analogs (CR rate 35-42%; NEJM 373:1733-1747, 2015). Moreover, minimal residual disease (MRD) was undetectable in the bone marrow biopsy and aspirate of 8/11 patients evaluated (73%), both by immunophenotyping and by allele-specific PCR (limit of detection: 0.05% BRAF-V600E copies). In 5 of these 8 patients, MRD clearing was reached even before sequential rituximab dosing post-vemurafenib. In the remaining 3/11 patients, MRD was at most 5% in 2 vemurafenib-naive patients, and 10% in 1 patient relapsed after prior BRAF-inhibitor treatment. In contrast, residual bone marrow disease was a constant feature of all 26 patients treated by us with vemurafenib alone for a longer time period (NEJM 373:1733-1747, 2015). CONCLUSIONS: This study - which is the first one combining vemurafenib and rituximab in relapsed/refractory HCL - suggests that this non-myelotoxic regimen produces more numerous, faster and deeper CRs than vemurafenib alone. Enrollment continues. Disclosures Gaidano: Karyopharm: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau.

Immune priming with nivolumab followed by nivolumab and rituximab in first-line treatment of follicular lymphoma: The phase 2 1st FLOR study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7560-7560
Author(s):  
Eliza Anne Hawkes ◽  
Sze Ting Lee ◽  
Geoff Chong ◽  
Michael Gilbertson ◽  
Andrew Grigg ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Response Rate ◽  
Nk Cell ◽  
Single Agent ◽  
Stage Iv ◽  
Complete Response ◽  
Phase 2 ◽  
Open Label ◽  
Immune Priming ◽  
Biomarker Analysis

7560 Background: Standard of care immunochemotherapy in front-line (1L) follicular lymphoma (FL) is highly efficacious but not without significant toxicity. High rates of grade 3-5 adverse events (AEs), primarily infection and bone marrow suppression, are experienced in up to 75% of patients. A more tolerable but equally effective approach is required. PD-1 inhibition, in combination with rituximab (R), increases T cell anti-tumour effect & enhances NK cell antibody dependent cell cytotoxicity, with proven efficacy in relapsed FL. The concept of ‘priming’ the immune system with nivolumab (N) prior to tumour-directed therapy has rationale and evidence, but the safety of this approach in 1L FL is not described. Methods: ‘1st FLOR’ (NCT03245021) is an open-label, multi-centre, phase 2, Simon’s 2-stage study of N + R (N = 39). Key eligibility were stage III-IV grade 1-3A FL requiring 1L systemic therapy; ECOG ≤2; adequate organ function. All patients (pts) receive induction N 240mg IV 2-weekly for 4 cycles. Pts with complete response (CR) receive 4 further cycles of 240mg IV N monotherapy then 12 cycles of maintenance N 480mg IV 4-weekly. Pts with < CR had 240mg N plus 375mg/m2 IV R 2-weekly for 4 cycles followed by maintenance N+R (N 480mg 4 weekly for 12 cycles; R 12 weekly for 8 cycles). Primary endpoint (EP) was ≥ G3 toxicity rate during induction. Secondary EPs; response rate by Lugano response criteria, overall toxicity, PFS, OS. Results: Between September 2017 to March 2020, 39 pts were enrolled. Baseline characteristics included median age of 54 (range: 28-79). stage IV disease in 67%, B Symptoms & bulk (≥7cm) in 23% each, intermediate-high risk FLIPI in 74%. The primary EP was met, with only 16 pts (41%) having ≥G3 toxicity at end of induction. Non-immune AEs were predominantly G1-2; most commonly infection (67%) & fatigue (64%). G3-4 Immune-related AEs were infrequent and included pancreatitis plus hepatitis (N = 1), pancreatitis alone (N = 1), rash (N = 1), transaminitis (N = 2), hypocortisolism (N = 1), hyperglycaemia (N = 3) and asymptomatic lipase/amylase increase (N = 3). Median follow-up was 17.5 months (range: 7-39). Overall response rate was 92% (36/39) with CR in 54% (21/39). Median time to CR was 5 months (m) (range: 2-25). Nine pts (23%) discontinued treatment; 7 due to progressive disease (1 pt died of transformed FL), 2 developed constitutional symptoms (1 stable disease, 1 partial response). In 25 evaluable pts, 12m PFS & OS is 72% (CI 51-88) & 96% (CI 80-100). Biomarker analysis is in progress. Conclusions: Immune-priming with single-agent N, then combination N+R in 1L FL is associated with favourable toxicity and high ORR & CR rates potentially providing an alternative to chemotherapy. Acknowledgements: Bristol-myers Squibb provided funding and nivolumab for this study. Clinical trial information: NCT03245021.

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