scholarly journals LGG-52. BINIMETINIB IN CHILDREN WITH PROGRESSIVE OR RECURRENT LOW-GRADE GLIOMA NOT ASSOCIATED WITH NEUROFIBROMATOSIS TYPE 1: INITIAL RESULTS FROM A MULTI-INSTITUTIONAL PHASE II STUDY

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii376-iii376
Author(s):  
Nathan Robison ◽  
Jasmine Pauly ◽  
Jemily Malvar ◽  
Sharon Gardner ◽  
Jeffrey Allen ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Dose Reduction ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Neurofibromatosis Type ◽  
Primary Objective ◽  
Preclinical Model ◽  
Low Grade ◽  
Type I ◽  
Open Label

Abstract BACKGROUND RAS/RAF/MEK/ERK pathway activation is the primary driver for most pediatric low-grade gliomas (LGG). Binimetinib is an orally bioavailable MEK1/2 inhibitor found to have significant central nervous system penetration in a preclinical model. OBJECTIVE The primary objective of this multi-institutional open-label phase II study was to assess preliminary efficacy of binimetinib in progressive pediatric LGG. The study included strata for both neurofibromatosis type I (NF1) and non-NF1 associated tumors, as well as a target validation (surgical) stratum. NF1 and surgical strata remain open to enrollment and will be reported separately. METHODS Children aged 1–18 years with previously treated recurrent or progressive LGG were eligible. The dose of binimetinib was 32 mg/m2/dose twice daily. Partial and minor responses were defined, respectively, as 50% and 25% decrease in maximal two-dimensional measurements. RESULTS Fifty-seven eligible patients without NF1, median age 8 years, were enrolled and began treatment; 26 were female; 28 had documented KIAA1549-BRAF fusion. Eleven patients discontinued drug in the first year due to toxicity, and an additional 27 required dose reduction. The most common drug-attributable grade 3 toxicities included creatine kinase elevation (n=9 patients), rash (n=8), and truncal weakness (n=8). Truncal weakness improved or resolved with dose reduction or cessation. Grade 4 toxicities included creatine kinase elevation (n=2) and transient colitis (n=1). Of 44 patients with preliminary response data available, 22 (50%) showed a minor (n=7) or partial (n=15) response. CONCLUSION Binimetinib is active, with manageable toxicities, in children without NF1 with progressive LGG.

scholarly journals Oral vinorelbine and cisplatin as first-line therapy for advanced squamous NSCLC patients: a prospective randomized international phase II study (NAVoTrial 03)

2021 ◽  
Vol 13 ◽  
pp. 175883592110229
Author(s):  
Francesco Grossi ◽  
Piotr Jaśkiewicz ◽  
Marion Ferreira ◽  
Grzegorz Czyżewicz ◽  
Dariusz Kowalski ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Current Knowledge ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Comparable Efficacy ◽  
Open Label ◽  
Oral Vinorelbine ◽  
First Line Therapy ◽  
Nsclc Patients

Objective: The study investigated the efficacy and safety of oral vinorelbine-cisplatin (OV-CDDP) and gemcitabine-cisplatin (GEM-CDDP) in patients with squamous non-small cell lung cancer (sq-NSCLC). Patients and methods: This was an open-label, prospective, multicenter, international phase II study that enrolled untreated patients with advanced sq-NSCLC. Patients were randomized to receive 3-week cycles of either 60–80 mg/m2 OV days 1 and 8 in combination with 80 mg/m2 CDDP day 1 (arm A) or 1250 mg/m2 GEM days 1 and 8 in combination with 75 mg/m2 CDDP day 1 (arm B). After four cycles, patients without disease progression continued maintenance dose of OV or GEM until progression or unacceptable toxicity. The primary objective was disease control rate (DCR). Secondary objectives included progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), safety, and quality of life (QoL). Results: A total of 114 patients with sq-NSCLC were randomized, and 113 were treated (57 in arm A and 56 in arm B). DCR was high in both arms: 73.7% (95%CI: 62.4–100.0) in arm A and 75.0% (95%CI: 63.7–100.0) in arm B. Median PFS and TTF were similar in arm A and B 4.2 and 2.8 months, and 4.3 and 3.1 months, respectively. Even though the difference was not significant, the OS was 10.2 for arm A and 8.4 months for arm B. The safety profiles were consistent with the current knowledge of adverse events. QoL results revealed an improvement in patients under OV treatment. Conclusion: The OV-CDDP combination showed comparable efficacy to GEM-CDDP with acceptable safety profile and enhanced patients’ QoL. Trial registration: The study was registered under EudraCT number 2012-003531-40.

An open-label international multicentric phase II study of nilotinib in progressive pigmented villo-nodular synovitis (PVNS) not amenable to a conservative surgical treatment.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 10516-10516 ◽  
Author(s):  
Hans Gelderblom ◽  
David Pérol ◽  
Christine Chevreau ◽  
Martin HN Tattersall ◽  
Silvia Stacchiotti ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Primary Tumour ◽  
Disease Stabilisation ◽  
Primary Objective ◽  
Neoplastic Disease ◽  
Open Label ◽  
Randomized Phase Ii ◽  
Maximum Sample Size ◽  
Grade 3

10516 Background: PVNS, also known as tenosynovial giant cell tumor (TGCT), is a rare pathological entity affecting the synovium in young adults. This neoplastic disease is driven by a t(1;2) translocation resulting in the fusion of COL6A3 and M-CSF genes. Nilotinib has inhibitory properties on M-CSF receptor pathway which could be of therapeutic interest in patient (pts) with non resectable PVNS. Methods: In this open-label international, multicentric, non-randomized, phase II study the primary objective is to evaluate the efficacy of nilotinib treatment (800 mg/day) in pts with progressive or relapsing PVNS not amenable to surgery or in whom surgery would be mutilating, as measured by the 12-week progression-free rate (12-w PFR) validated by an independent committee. Using a Bayesian design with a futility stopping rule and a maximum sample size set to 50 evaluable pts, interim analyses (IA) were planned after the inclusion of 10 and then every 5 pts. Results: From December 2010 to September 2012, 56 pts with progressive disease were enrolled by 17 institutions from Europe and Australia. Successive previous IA led to positive results in favour of the study continuation. 47 pts (median age 37 y (range: 18-74), 51% of males) were evaluable at the time of the last IA, with a median follow-up of 11.2 months (range: 0.6-12.7). Median time since diagnosis was 2.5 years (range: 0.02-26). Primary tumour was mainly located on knee (25 pts, 53%), hip (6 pts, 13%), ankle (6 pts, 13%). 4 pts had already received imatinib, 76% of pts had undergone a previous surgery. The 12-w PFR was 93.6% (95%CI, 82.5%-98.7%), without any OR. PR were observed later (2 at w-24 and 1 at w-48). Nilotinib was well tolerated, with only 4 pts experiencing grade 3 adverse events (anorexia: 1 pt; prurit: 1 pt; diarrhea: 1 pt; hepatic failure: 1 pt). 8 pts (17%) had a dose reduction and/or temporary discontinuation of nilotinib due to toxicity. Final results will be further presented. Conclusions: Nilotinib treatment induces disease stabilisation in a large proportion of PVNS patients with non resectable disease or in whom resection would be mutilating. Clinical trial information: NCT01261429.

A multicohort phase II study of durvalumab plus tremelimumab for the treatment of patients (PTS) with advanced neuroendocrine neoplasms (NENs) of gastroenteropancreatic (GEP) or lung origin (the DUNE trial-GETNE1601-).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS4146-TPS4146
Author(s):  
Ignacio Matos Garcia ◽  
Enrique Grande ◽  
Rocio Garcia-Carbonero ◽  
Carlos Lopez ◽  
Alexandre Teule ◽  
...  
Keyword(s):  
Phase Ii ◽  
Primary Endpoint ◽  
Phase Ii Study ◽  
Progression Free Survival ◽  
Tumor Growth Rate ◽  
Neuroendocrine Neoplasms ◽  
Low Grade ◽  
Open Label ◽  
Platinum Based Chemotherapy ◽  
Tumor Load

TPS4146 Background: NENs include a heterogeneous group of tumors with different behavior. Despite immunomodulators such as interferon are approved for the management of grade 1-2 NENs, the low mutation tumor load and PD-1/PDL-1 expression have limited the development of immune check-point inhibitors in this setting. The rational for immunotherapy in high grade NENs is stronger compared with low grade NENs based on the results observed in small cell lung cancer. However, the combination of an antiPDL-1 and antiCTLA-4 could increase the probability of success regardless of tumor growth rate, mutational tumor load or PDL-1 expression in low grade NENs. Methods: This prospective, multi-center, open label, phase II study (EudraCT:2016-002858-20) will evaluate the efficacy and safety of durvalumab plus tremelimumab in 126 pts within four different cohorts, including well-moderately differentiated lung NENs (Cohort 1), grade 1-2 gastrointestinal NENs (Cohort 2), grade 1-2 pancreatic NENs (Cohort 3) and grade 3 GEP NENs (Cohort 4). To optimize the efficacy of immunotherapy in low grade NENs, pts included in the trial must have progressed to all standard approved therapy in each setting, including somatostatin analogues, targeted agents and chemotherapy for lung and GEP grade 1-2 NENs up to 4 prior lines. For pts included in cohort 4, progression to standard platinum-based chemotherapy is mandatory. All pts will receive durvalumab 1500 mg every 28 days for 12 months, and tremelimumab 75 mg Q4W up to 4 doses/cycles. Retreatment is allowed after disease progression in the follow-up period. The primary endpoint of the study for cohorts 1-3 is disease control rate at 9 months including the percentage of pts achieving complete response, partial response, or stable disease according to RECIST v1.1; Median overall survival will be the primary endpoint for cohort 4. Primary endpoints will be assessed by investigators and confirmed by central radiological review. Secondary endpoints include median progression-free survival, safety and tolerability and a wide panel of biomarkers in blood samples and tumor tissue. Clinical trial information: 2016-002858-20.

Phase II study of fluorouracil (FU), leucovorin (LV), and nanoliposomal irinotecan (nal-IRI) in previously treated advanced biliary tract cancer (NAPOLI-2).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. TPS593-TPS593
Author(s):  
Benjamin Adam Weinberg ◽  
Hongkun Wang ◽  
Katrina Pedersen ◽  
Amikar Sehdev ◽  
Max W. Sung ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Dropout Rate ◽  
Primary Objective ◽  
Second Line ◽  
Current Standard ◽  
Primary Analysis ◽  
Open Label ◽  
Previously Treated

TPS593 Background: Biliary tract cancers (BTCs) are rare and aggressive malignancies. The current standard of care for advanced BTC is gemcitabine (GEM) plus cisplatin . Although there is no established second-line treatment, regimens such as FOLFOX, XELOX, FOLFIRI, XELIRI, GEM, and capecitabine have activity. Nal-IRI contains IRI free base encapsulated in liposome nanoparticles which shelter IRI from conversion to its active metabolite (SN-38) and increase intratumoral levels of SN-38 compared with IRI. FU/LV/nal-IRI has shown overall survival benefit and acceptable toxicity in patients (pts) with metastatic pancreatic adenocarcinoma following GEM-based therapy in the NAPOLI-1 trial. Methods: This is a single arm, open label, multicenter phase II study of pts with advanced BTC previously treated with gemcitabine plus platinum chemotherapy. Pts will receive nal-IRI 70 mg/m2 IV over 90 minutes, LV 400 mg/m2 IV over 30 minutes, and FU 2400 mg/m2 over 46 hours, every 14 days. The primary objective is to determine progression-free survival (PFS) rate at 4 months (4mo) using RECIST v. 1.1 criteria and central radiology review. Response assessments will occur using imaging every 8 weeks. All pts who receive at least 1 dose of the study treatment will be eligible for the primary analysis. We will substitute pts who screen fail or do not begin treatment. Median PFS reported for pts receiving second-line 5-FU doublet chemotherapy is 3 months with a PFS4mo of 30%. FU/LV/nal-IRI would be of interest if it could increase the PFS4mo to 50% or higher. We will use a 2-stage Simon Minimax design. Using a one-sided α of 0.05 and 80% power, 39 pts will be required to detect a difference in PFS4mo between 30% and 50%. Assuming a dropout rate of 10%, 44 pts will be enrolled across the 5 study sites. Enrollment began in Q2 2019. Clinical trial information: NCT04005339.

A randomized, open-label phase II study of single-agent vintafolide versus vintafolide plus docetaxel versus docetaxel alone in second-line NSCLC patients with all target lesions expressing folate-receptor (TARGET).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS8125-TPS8125
Author(s):  
Martin J. Edelman ◽  
Hong Ma ◽  
Wendy Perez ◽  
Alex A. Adjei ◽  
Nasser Hanna
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Folate Receptor ◽  
Single Agent ◽  
Primary Objective ◽  
Second Line ◽  
Open Label ◽  
Histologic Diagnosis ◽  
Potential Biomarker ◽  
Open Label Phase

TPS8125 Background: Folate receptor (FR) is frequently overexpressed in NSCLC and is a potential biomarker for therapy selection. Vintafolide (EC145) is designed to target FR expressing cells and consists of folate linked to desacetylvinblastinehydrazide. The FR targeted imaging agent, 99mTc-etarfolatide (EC20), consists of folate coupled to technetium and identifies lesions that overexpress FR which may respond to vintafolide treatment. A phase II study of single-agent vintafolide in heavily pre-treated lung adenocarcinoma patients (pts) showed promising activity in clinical benefit response (50% vs. 14.3%) and overall survival (OS, 47.2 wks vs. 14.9 wks), in pts whose target lesions all expressed FR [FR (100%)] vs pts whose target lesions were not all FR positive (Edelman et al, JTO 2012:7:1618-21). This trial assesses the benefit of vintafolide as second-line therapy in NSCLC FR (100%) pts. Methods: This is a randomized, open-label phase II study of vintafolide vs. vintafolide + docetaxel vs. docetaxel in second line NSCLC FR (100%) pts ( NCT01577654 ). Key eligibility criteria include: cytologic or histologic diagnosis of NSCLC, 1 prior systemic therapy for advanced disease, and PS 0-1. At baseline, pts undergo 99mTc-etarfolatide imaging to detect FR-positive lesions. FR (100%) pts are randomized 1:1:1 to vintafolide, vintafolide + docetaxel, or docetaxel. Vintafolide (2.5 mg) is administered on d 1, 4, 8, and 11 of a 3-wk cycle. Docetaxel (75 mg/m2) is given on d 1 of a 3-wk cycle. Treatment continues until disease progression or unacceptable toxicity. Pts receiving vintafolide + docetaxel who discontinue docetaxel due to toxicity may continue vintafolide alone. Disease status is evaluated by RECIST v1.1 criteria every 6 wks and adverse events are monitored throughout. The primary objective of this study compares PFS between the docetaxel control arm and each experimental arm with the goal of demonstrating a hazard ratio of ≤0.67 favoring the experimental arms. Secondary objectives include response rate, disease control rate, OS, and safety/tolerability. Enrollment to the study is ongoing. Clinical trial information: NCT01577654.

A phase II study of BP1001 (liposomal Grb2 antisense oligonucleotide) in patients with hematologic malignancies.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS7561-TPS7561
Author(s):  
Maro Ohanian ◽  
Tara L. Lin ◽  
Michael Craig ◽  
Apurv Agrawal ◽  
Kathleen Halka ◽  
...  
Keyword(s):  
High Risk ◽  
Complete Remission ◽  
Phase Ii ◽  
Antisense Oligonucleotide ◽  
Residual Disease ◽  
Phase Ii Study ◽  
Primary Objective ◽  
Molecular Characteristics ◽  
Open Label ◽  
Historical Comparison

TPS7561 Background: The growth factor receptor bound protein-2 (Grb2) is vital to oncogene signaling and tumor progression. BP1001 is a liposome-incorporated Grb2 antisense oligonucleotide that inhibits Grb2 expression. Grb2 inhibition suppresses cancer growth and survival. A Phase I/Ib single center study in patients with refractory/relapsed leukemias demonstrated the safety of BP1001 up to 90 mg/m2 dose and the efficacy of BP1001 in combination with low dose cytarabine (LDAC) in refractory/relapsed acute myeloid leukemia (AML) patients (Ohanian, Lancet Haematol 2018). Based on pharmacokinetic (PK) considerations, the recommended Phase II dose was 60 mg/m2. A phase II study was initiated to explore the clinical impact of BP1001 in combination with LDAC in untreated AML patients. Interim safety and efficacy of BP1001 + LDAC in untreated AML patients was presented at the 2018 Annual ASH Meeting. BP1001 was safely administered to 25 patients with untreated AML, who were considered unfit for standard chemotherapy. Efficacy data compared favorably to what has been reported with available options for unfit patients largely with secondary AML or adverse-risk AML. Since the Interim Data presentation, the study was amended to investigate BP1001 + decitabine combination and include myelodysplastic syndrome (MDS) patients. This is because BP1001 enhanced decitabine anti-leukemic effects in preclinical studies. Methods: This is a multi-center, open-label study with 2 parallel cohorts of BP1001 + decitabine treatment in untreated AML/high risk MDS patients and refractory/relapsed AML/high risk MDS patients who are considered by the investigator unsuitable for or refused intensive chemotherapy. BP1001 is given intravenously (IV) at 60 mg/m2 twice weekly. Decitabine is given 20 mg/m2 IV daily for 5 consecutive days. Each cycle is 28 days. Each cohort can enroll 19 patients, with a decision to stop or proceed to 54 patients. The primary objective of this study is to assess whether BP1001 + decitabine provides higher complete remission rates than decitabine alone (by historical comparison) in AML/high risk MDS patients. The secondary objectives of this study are to assess: Safety of BP1001 + decitabine; partial remissions and blast count reductions; overall survival, time to response and duration of response; minimal residual disease status in patients who achieve complete remission; and plasma PK profile of BP1001. The exploratory objective of this study is to evaluate the association of treatment response with cytogenetic and molecular characteristics. Clinical trial information: NCT02781883 .

Bortezomib With or Without Irinotecan in Relapsed or Refractory Colorectal Cancer: Results From a Randomized Phase II Study

2008 ◽  
Vol 26 (14) ◽  
pp. 2320-2326 ◽  
Author(s):  
Peter S. Kozuch ◽  
Caio Max Rocha-Lima ◽  
Tomislav Dragovich ◽  
Howard Hochster ◽  
Bert H. O'Neil ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adverse Events ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Sensory Neuropathy ◽  
Primary Objective ◽  
Response To Treatment ◽  
Open Label ◽  
Open Label Phase ◽  
Grade 3

PurposeTo evaluate the efficacy and toxicity of bortezomib with or without irinotecan, in patients with relapsed or refractory colorectal cancer (CRC).Patients and MethodsPatients were randomly assigned in a 3:4 ratio to bortezomib 1.5 mg/m2(arm A) or bortezomib 1.3 mg/m2plus irinotecan 125 mg/m2(arm B). A treatment cycle of 21 days consisted of four bortezomib doses on days 1, 4, 8, and 11, plus, in arm B, irinotecan on days 1 and 8. The primary objective of this randomized, multicenter, open-label, phase II study was to determine tumor response to treatment. Secondary objectives were safety and tolerability.ResultsA preplanned interim analysis to assess efficacy revealed inadequate activity, resulting in early termination of this study. A total of 102 patients were treated, 45 in arm A and 57 in arm B. Baseline characteristics were comparable. The investigator-assessed response rate was 0 in arm A and 3.5% in arm B (all partial responses). Adverse events in both treatment arms were as expected, with no significant additive toxicity. The most common grade ≥ 3 adverse events reported, per patient, during the study were fatigue (27%), vomiting (13%), nausea (11%), and peripheral sensory neuropathy (11%) in arm A, and diarrhea (33%), fatigue (25%), neutropenia (23%), thrombocytopenia (18%), dyspnea (12%), abdominal pain (12%), dehydration (12%), and anemia (11%) in arm B.ConclusionBortezomib alone or in combination with irinotecan was not effective in patients with relapsed or refractory CRC.

An open-label international multicentric phase II study of nilotinib in progressive pigmented villo-nodular synovitis (PVNS) not amenable to a conservative surgical treatment.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10006-10006 ◽  
Author(s):  
Isabelle Ray-Coquard ◽  
Hans Gelderblom ◽  
Christine Chevreau ◽  
Judith R. Kroep ◽  
Antoine Italiano ◽  
...  
Keyword(s):  
Phase Ii ◽  
Interim Analysis ◽  
Phase Ii Study ◽  
Primary Tumour ◽  
Disease Stabilisation ◽  
Primary Objective ◽  
Neoplastic Disease ◽  
Open Label ◽  
Randomized Phase Ii ◽  
Grade 3

10006 Background: PVNS, also known as tenosynovial giant cell tumor (TGCT), is a rare pathological entity affecting the synovium in young adults. This neoplastic disease is driven by a t(1;2) translocation which results in the fusion of COL6A3 and M-CSF genes. Nilotinib has inhibitory properties on M-CSF receptor pathway which could be of therapeutic interest in pts with non resectable PVNS. Methods: In this open-label International, multicenter, non-randomized, phase II study the primary objective is to evaluate the efficacy of nilotinib treatment in patients (pts) with progressive or relapsing PVNS not amenable to surgery or in whom surgery would be mutilating, as measured by the 12-week progression-free rate (12-w PFR) validated by an independent committee. Using a Bayesian design with a stopping rule for futility, interim analyses were planned after the inclusion of 10 pts and then every 5 pts. Results: From December 2010 to November 2011, 33 pts with progressive disease from 17 institutions from Europe and Australia were enrolled. 14 pts (median age 37 y (range: 19-68), 7 males) were analyzed in the 2nd interim analysis. Median time since diagnosis was 4.4 years (range: 0.2-26). Primary tumour was located on a knee for 10 pts (71%) and on hip (1 pt, 7%), finger (7%), foot (7%), hand (7%), respectively. 69% of pts had a inoperable PVNS and 31% had a resectable tumour but requiring mutilating surgery. All pts started nilotinib at the planned dose of 800 mg/day. At a median follow-up of 8.9 months (range: 0.6-11), 2 pts had a dose reduction and 1 pt had discontinued nilotinib after 14 days due to toxicity. Nilotinib was well tolerated, with only 2 pts experiencing grade 3 adverse events (anorexia: 1 pt; hepatic failure: 1 pt).The 12-w PFR was 85.7% (95%CI, 57.2%-98.2%), in favour of the study continuation. No OR was observed at w-12; 1 pt (7%) was in PR at w-30. Updated results will be presented after the 3rd interim analysis. Conclusions: Nilotinib treatment induces disease stabilisation in a large proportion of PVNS patients with non resectable disease or in whom resection would be mutilating.

Basket study of the oral progesterone antagonist onapristone ER in women with progesterone receptor positive (PR+) recurrent granulosa cell tumor (GCT), low-grade serous ovarian cancer (LGSOC), or endometrioid endometrial cancer (EEC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS6098-TPS6098
Author(s):  
Rachel N. Grisham ◽  
Karen Li ◽  
Alexia Iasonos ◽  
Jeffrey Girshman ◽  
Karen Anne Cadoo ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Primary Objective ◽  
Stage I ◽  
Cancer Center ◽  
Low Grade ◽  
Type I ◽  
Open Label ◽  
Dose Escalation Study ◽  
Recist 1.1 ◽  
Progesterone Antagonist

TPS6098 Background: Onapristone extended release (ER) is a type I full progesterone antagonist that inhibits progesterone mediated PR activation and stabilizes PR association with corepressors. Onapristone has shown activity across multiple preclinical models of hormonally driven cancer. A phase I dose escalation study of onapristone ER in PR+ breast, endometrial and ovarian cancer patients found all doses tested to be well tolerated, with 50mg PO BID determined to be the recommended phase 2 dose (RP2D). GCT (98% of cases PR+), LGSOC (58% of cases PR+) and EEC (67% of cases PR+) are hormonally driven cancers which generally have poor responses to chemotherapy and limited treatment options in the recurrent setting. Methods: This is an open-label, investigator-initiated basket study of onapristone ER in patients with PR+ recurrent GCT, LGSOC, or EEC currently enrolling patients at Memorial Sloan Kettering Cancer Center in NY, USA (NCT03909152). The primary objective is to evaluate the efficacy, in terms of response rate by RECIST 1.1 criteria, within 36 weeks of treatment. Eligible patients must have received at least 1 prior line of chemotherapy, have measurable disease by RECIST 1.1 criteria, and have tumor tissue collected within 3 years prior to enrollment with PR expression ≥ 1% by IHC. Patients are allowed to have unlimited additional prior lines of chemotherapy, biologic therapy, immunotherapy or hormonal therapy. Enrolled patients are treated with onapristone ER 50mg PO BID until time of progression or intolerable toxicity. The 3 disease cohorts are currently enrolling to Stage I in parallel with expansion from stage I to stage II planned when the prespecified response criteria are met for each cohort as described in the table below. Clinical trial information: NCT03909152. [Table: see text]

COMBI-MB: A phase II study of combination dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600–mutant (mut) melanoma brain metastases (MBM).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9506-9506 ◽  
Author(s):  
Michael A. Davies ◽  
Caroline Robert ◽  
Georgina V. Long ◽  
Jean Jacques Grob ◽  
Keith T. Flaherty ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Phase Ii Study ◽  
Local Treatment ◽  
Mek Inhibitor ◽  
Primary Objective ◽  
Clinical Activity ◽  
Open Label ◽  
Safety Issues ◽  
Open Label Phase

9506 Background: CNS metastases are common and associated with very poor prognosis in pts with metastatic melanoma (MM). In the phase II BREAK-MB trial, D had clinical activity in BRAF V600–mut MBM. D + T has shown superiority over D alone in pts with BRAF V600–mut mm without MBM; however, efficacy of this regimen on MBM has not been characterized. Here, we report results from a phase II trial of D + T in BRAFV600–mut MBM (COMBI-MB; NCT02039947). Methods: This open-label, phase II study evaluated D 150 mg BID + T 2 mg QD in 4 MBM cohorts: (A) BRAFV600E, asymptomatic MBM, no prior local treatment (Tx); (B) BRAFV600E, asymptomatic MBM, prior local Tx; (C) BRAFV600D/K/R, asymptomatic MBM, with or without prior local Tx; and (D) BRAFV600D/E/K/R, symptomatic MBM, with or without prior local Tx. The primary objective was intracranial response rate (IRR) in cohort A (null hypothesis, IRR ≤ 35%). Secondary endpoints included IRR in cohorts B, C, and D; extracranial (ERR) and overall (ORR) response rates; intracranial (IDCR), extracranial (EDCR), and overall (ODCR) disease control rates; duration of IR, ER, and OR; PFS; OS; and safety. Results: 125 pts were enrolled (A, n = 76; B, n = 16; C, n = 16; D, n = 17). In cohort A, median age was 52, 53% were male, and 37% had LDH > ULN. At data cutoff (28 Nov 2016; median f/u, 9.0 mo), in cohort A, investigator-assessed IRR was 58% (IDCR, 78%), ERR was 55% (EDCR, 80%), and ORR was 58% (ODCR, 80%). Median duration of IR, ER, and OR was 6.5 mo (95% CI, 4.9-10.3), 10.2 mo (95% CI, 6.5-13.0), and 6.5 mo (95% CI, 4.9-10.3), respectively. Median PFS was 5.6 mo (95% CI, 5.3-7.4). Independent review supported these results. 6-mo OS was 79%; with 31 pts (41%) still in f/u, preliminary median OS was 10.8 mo (95% CI, 8.7-19.6). Efficacy in cohorts B, C, and D will be reported. AEs across cohorts (any, 98%; grade 3/4, 48%) were consistent with prior D + T studies; 10% of pts (8% in cohort A) discontinued due to AEs. Conclusions: In this first report of a phase II trial evaluating a BRAF and MEK inhibitor combination in BRAFV600–mut MBM, the primary endpoint was met. Promising IRR and IDCR were seen with D + T, but responses appear less durable than reported for mm without MBMs. No unexpected safety issues were observed. Clinical trial information: NCT02039947.

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