Solid Tumors Harboring a BRAF V600 Mutation Clinical Trial
Official title:
A Phase Ib/II, Multicenter, Open-label, Dose Escalation Study of LGX818 in Combination With MEK162 in Adult Patients With BRAF V600 - Dependent Advanced Solid Tumors
| Verified date | February 2024 |
| Source | Pfizer |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
This is a multi-center, open-label, dose finding, Phase Ib dose escalation study to estimate the MTD(s) and/or RP2D(s) for the dual combination of LGX818 and MEK162 and the triple combination of LGX818 and MEK162 and LEE011, followed each independently by a Phase II part to assess the clinical efficacy and to further assess the safety of the combinations in selected patient populations. Oral LGX818 and MEK162 will be administered on a continuous schedule. Oral LEE011 will be administered once daily on a three weeks on, one week off schedule. Patients will be treated until progression of disease, unacceptable toxicity develops, or withdrawal of informed consent, whichever occurs first. A cycle is defined as 28 days. The dose escalation parts of the trial will be conducted in adult patients with BRAF V600-dependent advanced solid tumors and is expected to enroll at least 18 patients for the dual combination and at least 12 patients for the triple combination. The dose escalation will be guided by a Bayesian logistic regression model (BLRM). Following MTD/RP2D declaration, patients will be enrolled in three Phase II arms for the dual combination and one Phase II arm for the triple combination. All patients will be followed for 30 days for safety assessments after study drugs discontinuation. All patients enrolled in the Phase II part of the study will be followed for survival.
| Status | Completed |
| Enrollment | 189 |
| Est. completion date | March 9, 2023 |
| Est. primary completion date | March 9, 2023 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years and older |
| Eligibility | Inclusion Criteria: Histologically confirmed diagnosis of locally advanced or metastatic melanoma (stage IIIB to IV per American Joint Committee on Cancer [AJCC]), or confirmed diagnosis of non-resectable advanced metastatic colorectal cancer (mCRC), or any other indication upon agreement with the Sponsor, whose disease has progressed despite previous antineoplastic therapy or for whom no further effective standard therapy is available - Written documentation of BRAF V600E mutation, or any other BRAF V600 mutation - Evidence of measurable disease as determined by RECIST v1.1 - World Health Organization (WHO) Performance Status = 2 - Negative serum pregnancy test within 72 hours prior to the first study dose in all women of childbearing potential Exclusion Criteria: Progressive disease following prior treatment with RAF-inhibitors in combination with MEK-inhibitors - Symptomatic or untreated leptomeningeal disease - Symptomatic brain metastases. Patients are not permitted to receive enzyme inducing anti-epileptic drugs - Known acute or chronic pancreatitis - History or current evidence of retinal disease, retinal vein occlusion or ophthalmopathy - Clinically significant cardiac disease - Patients with abnormal laboratory values at Screening/baseline - Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral LGX818/MEK162 - Previous or concurrent malignancy - Pregnant or nursing (lactating) women - For addition of LEE011 in the triple combination, congenital long QT syndrome or family history of unexpected sudden cardiac death and/or hypokalemia CTCAE Grade = 3, brain metastases at baseline, abnormal coagulation results PT/INR >1.5 x ULN or aPTT >1.5 x ULN. Other protocol-defined inclusion/exclusion criteria may apply |
| Country | Name | City | State |
|---|---|---|---|
| Australia | Chris O'Brien Lifehouse Hospital | Camperdown | New South Wales |
| Australia | Melanoma Institute Australia | North Sydney | New South Wales |
| Australia | Melanoma Institute Australia | North Sydney | |
| Australia | Westmead Hospital-Redbank Rd | Northmead | New South Wales |
| Australia | Westmead Hospital | Westmead | New South Wales |
| Australia | Westmead Hospital-Redbank Rd | Westmead | New South Wales |
| Belgium | UZ Leuven- Gasthuisberg Campus | Leuven | Vlaams Brabant |
| Canada | Sir Mortimer B. Davis-Jewish General Hospital | Montreal | Quebec |
| France | Hôpital Saint louis | Paris | |
| France | Service de radiologie - Hopital Saint Louis | Paris | |
| Italy | ASST Grande Ospedale Metropolitano Niguarda - Presidio Ospedaliero Ospedale Niguarda Ca' Granda | Milan | |
| Italy | IRCCS Fondazione Pascale | Naples | Campania |
| Italy | Azienda Ospedaliera Monaldi | Napoli | Campania |
| Italy | Azienda Ospedaliera Universitaria Federico II | Napoli | Campania |
| Italy | Istituto Nazionale per lo studio e la cura dei tumori Fondazione Giovanni Pascale | Napoli | |
| Singapore | National Cancer Centre Singapore | Singapore | |
| Spain | Hospital Universitario Vall d'Hebrón - PPDS | Barcelona | |
| Spain | Hospital Universitario HM Sanchinarro ? CIOCC | Madrid | |
| Switzerland | Kantonsspital St. Gallen | St.Gallen | |
| Switzerland | University Hospital Zürich, Dermatology | Zurich-Airport | Zurich |
| United States | Johns Hopkins Sidney Kimmel Comprehensive Cancer Center | Baltimore | Maryland |
| United States | Massachusetts General Hospital | Boston | Massachusetts |
| United States | Ophthalmic Consultants of Boston Inc (OCB) | Boston | Massachusetts |
| United States | The University of Texas MD Anderson Cancer Center | Houston | Texas |
| United States | H. Lee Moffitt Cancer Center & Research Institute, Inc. | Tampa | Florida |
| United States | Moffitt McKinley Outpatient Center | Tampa | Florida |
| Lead Sponsor | Collaborator |
|---|---|
| Pfizer |
United States, Australia, Belgium, Canada, France, Italy, Singapore, Spain, Switzerland,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Number of Participants With Dose Limiting Toxicities (DLTs): Phase 1b | DLT was defined as an adverse event or abnormal laboratory value assessed as at least possibly related to the study medication, as clinically relevant, as unrelated to disease, disease progression, inter-current illness, or concomitant medications, which occurred (less than equal to) <=28 days following the first dose of LGX818 and MEK162 or LGX818 and MEK162 and LEE011 (cycle 1) and met the defined criteria for the study. | Phase 1b: Cycle 1 (28 days following the first dose of LGX818 and MEK162 or LGX818 and MEK162 and LEE011) | |
| Primary | Disease Control Rate (DCR) at Week 16: Phase 2, Arm 1 (mCRC Participants) | DCR was defined as percentage of participants with a best overall response of complete response (CR), partial response (PR) or stable disease (SD). As per Response Evaluation Criteria in Solid tumors Response Evaluation Criteria in Solid Tumors (RECIST) v1.1: CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must have a reduction in short axis less than (<)10 millimeter [mm]). PR was defined as more than equal to (>=) 30 percent (%) decrease under baseline of sum of diameters of all target lesions taking as reference the baseline sum of diameters. SD was defined as neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease (PD). | Phase 2: Week 16 | |
| Primary | Objective Response Rate (ORR): Phase 2, Arms 2, 3 and A | ORR was defined as the percentage of participants with a best overall response of CR or PR. As per RECIST v1.1, CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must have a reduction in short axis <10 mm. PR was defined as >= 30% decrease under baseline of sum of diameters of all target lesions taking as reference the baseline sum of diameters. | Phase 2: From Day 1 of dosing till complete response or partial response achieved (maximum exposure of treatment for Phase 2 was 111.5 months] | |
| Secondary | Number of Participants With Treatment Emergent Adverse Events (TEAEs): Overall Grades and AEs of Grade 3/4: Phase 1b | An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were those events with onset dates occurring during the on-treatment period (the time from the Day 1 up to 30 days after last dose). AEs were graded according to National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 as Grade 1 indicates Mild AE, Grade 2 indicates Moderate AE, Grade 3 indicates severe AE, and grade 4 indicates life-threatening consequences; urgent intervention indicated. Grade 5 indicates death related to AE. | Phase 1b: Day 1 up to 30 days after last dose (maximum treatment exposure for Phase 1b was 118.3 months) | |
| Secondary | Number of Participants With TEAEs: Overall Grades and AEs of Grade 3/4: Phase 2 | An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were those events with onset dates occurring during the on-treatment period (the time from the Day 1 up to 30 days after last dose). AEs were graded according to CTCAE version 4.03 as Grade 1 indicates Mild AE, Grade 2 indicates Moderate AE, Grade 3 indicates severe AE, and grade 4 indicates life-threatening consequences; urgent intervention indicated. Grade 5 indicates death related to AE. | Phase 2: Day 1 up to 30 days after last dose (maximum treatment exposure for Phase 2 was 111.5 months) | |
| Secondary | Area Under the Concentration-time Curve From Time Zero to Infinity With Extrapolation of the Terminal Phase (AUCinf) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b | AUCinf was reported in unit of measure as hour*nanogram per millilitre (h*ng/mL). | Phase 1b: Pre dose, 0.5,1.5,2.5,4,6,8 and 24 hours (hr) post dose on Day 1 of Cycle 1 | |
| Secondary | Area Under the Concentration-Time Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b | Phase 1b: Pre dose, 0.5,1.5,2.5,4,6,8 and 24 hr post dose on Day 1 of Cycle 1 | ||
| Secondary | AUClast at Steady State (AUClast,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b | Phase 1b: Pre dose,0.5,1.5, 2.5,4,6,8 and 24 hr post dose on Day 15 of Cycle 1 | ||
| Secondary | Area Under the Concentration-Time Curve From Time Zero to Tau After First Dose (AUCtau) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b | Phase 1b: Pre dose, 0.5,1.5,2.5,4,6,8 and 24 hr post dose on Day 1 of Cycle 1 | ||
| Secondary | AUCtau at Steady State (AUCtau,ss) of Encorafenib, Binimetinib and Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b | Phase 1b: Pre dose,0.5,1.5, 2.5,4,6,8 and 24 hr post dose on Day 15 of Cycle 1 | ||
| Secondary | Maximum Observed Plasma Concentration (Cmax) of Encorafenib, Binimetinib, Ribociclib Metabolite of Binimetinib and Ribociclib: Phase 1b | Phase 1b: Pre dose, 0.5,1.5,2.5,4,6,8 and 24 hr post dose on Day 1 of Cycle 1 | ||
| Secondary | Cmax at Steady State (Cmax,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b | Phase 1b: Pre dose,0.5,1.5,2.5,4,6,8 and 24 hr post dose on Day 15 of Cycle 1 | ||
| Secondary | Elimination Half-life (t1/2) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b | Phase 1b: Pre dose, 0.5,1.5,2.5,4,6,8 and 24 hr post dose on Day 1 of Cycle 1 | ||
| Secondary | t1/2 at Steady State (t1/2,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b | Phase 1b: Pre dose,0.5,1.5,2.5,4,6,8 and 24 hr post dose on Day 15 of Cycle 1 | ||
| Secondary | Accumulation Ratio (RA) of Encorafenib, Binimetinib, Ribociclib Metabolite of Binimetinib and Ribociclib: Phase 1b | Accumulation ratio was calculated as AUCtau,ss/AUCtau. | Phase 1b: Pre dose, 0.5,1.5,2.5,4,6,8 and 24 hr post dose on Day 1 and 15 of Cycle 1 | |
| Secondary | Objective Response Rate (ORR): Phase 1b | ORR was defined as the percentage of participants with a best overall response of CR or PR. As per RECIST v1.1, CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must have a reduction in short axis <10 mm. PR was defined as >= 30 % decrease under baseline of sum of diameters of all target lesions taking as reference the baseline sum of diameters. | Phase 1b: From Day 1 of dosing till complete response or partial response achieved (maximum exposure of treatment in Phase 1b was 118.3 months) | |
| Secondary | Progression Free Survival (PFS): Phase 2 | PFS was defined as the time from the start of study treatment to the date of the event defined as the first documented progression or death due to any cause. If a participant did not have an event, PFS was censored at the date of last adequate tumor assessment. Per RECIST 1.1, PD= At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm^2. Unequivocal progression of existing non-target lesions. Kaplan-Meier method was used for analysis. | Phase 2: From start of study drug until documented PD or death due to any cause or censoring date (maximum exposure of treatment in Phase 2 was 111.5 months) | |
| Secondary | Time to Response (TTR): Phase 2 | TTR was defined as the time from the first dose of study treatment to the first documentation of objective tumor response documented in participants with confirmed objective response (CR or PR). As per RECIST v1.1, CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must have a reduction in short axis <10 mm. PR was defined as >= 30 % decrease under baseline of sum of diameters of all target lesions taking as reference the baseline sum of diameters. Kaplan-Meier method was used for analysis. | Phase 2: From date of start of treatment until date of first documentation of objective tumor response (maximum exposure of treatment in Phase 2 was 111.5 months) | |
| Secondary | Duration of Response (DOR): Phase 2 | DOR was defined as the time from the first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to underlying cancer, whichever occurred first in participants with confirmed objective response (CR or PR). As per RECIST v1.1, CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must have a reduction in short axis <10 mm. PR was defined as >= 30 % decrease under baseline of sum of diameters of all target lesions taking as reference the baseline sum of diameters. Kaplan-Meier method was used for analysis. | Phase 2: From date of first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to underlying cancer, whichever occurred first (maximum exposure of treatment in Phase 2 was 111.5 months) | |
| Secondary | Overall Survival (OS): Phase 2 | OS was defined as the time from date of randomization/start of treatment to date of death due to any cause. If a participant was not known to have died, survival was censored at the date of last contact. Analysis was performed using Kaplan-Meier method. | Phase 2: From date of start of study treatment until date of death or censoring date (maximum exposure of treatment in Phase 2 was 111.5 months) | |
| Secondary | Number of Participants With Molecular Alterations of Tumor Tissues Using Potential Predictive Markers: Phase 1b | Molecular alterations of tumor tissues was determined using the following potential predictive markers: Biomarkers like V-raf murine sarcoma viral oncogene homolog B1 (BRAF),V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), Phosphatase and tensin homolog (PTEN), Phosphatidylinositol 3' kinase catalytic alphapolypeptide (PIK3CA), Epidermal growth factor receptor (EGFR). | Phase 1b: Baseline | |
| Secondary | Number of Participants With Molecular Alterations of Tumor Tissues Using Potential Predictive Markers: Phase 2 | Molecular alterations of tumor tissues was determined using the following potential predictive markers: BRAF, HRAS, KRAS, Neuroblastoma RAS viral oncogene homolog (NRAS), PTEN, PIK3CA, Mitogen-activated protein kinase 1 (MAP2K1), Mitogen-activated protein kinase 2 (MAP2K2), EGFR. | Phase 2: Baseline |