BRAF/MEK/EGFR Inhibitor Combination Study in Colorectal Cancer (CRC)

NCT01750918 | Completed Phase 1 Results FDA Drug

• 3 other identifiers: 116833CDRB436C22012012-004802-81
• Study Type: interventional
• Target: 166
• Locations: 8 countries
• Sites: 20

Brief Summary

This was a four part, phase I/II study aimed to evaluate the safety, tolerability and efficacy of combination of an anti-EGFR antibody panitumumab (P) either with a BRAF inhibitor (dabrafenib (D); GSK2118436) alone or with the combination of a BRAF inhibitor and a MEK inhibitor (trametinib (T); GSK1120212) in patients with BRAF-mutant V600E advanced or mCRC. The goal was to: 1) Determine RP2R/MTD for doublet (D+P) and triplet (D+T+P) combinations in Part 1; 2) Assess clinical activity for these combinations in Part 2; 3) Determine RP2R/MTD for double (T+P) combination in Part 4A, and assess clinical activity of this combination in two patient populations in Part 4B (patients with BRAF-V600E mutation-positive advanced or metastatic CRC and patients with advanced or metastatic CRC with secondary resistance to anti-EGFR therapy).

Conditions

Cancer

Keywords

MEK inhibitor; anti-EGFR antibody; colorectal cancer; BRAF inhibitor

Outcome Measures

Primary Outcomes (3)

• Number of Participants With Adverse Events

  The distribution of adverse events was done via the analysis of frequencies for Adverse Events, Serious Adverse Events and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. Only descriptive analysis performed.

  From study treatment start date till 30 days safety follow-up, assessed up to approximately 90 months

• Overall Response Rate (ORR)

  Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) was used for efficacy based on radiological assessment of tumor burden: CR = Complete Response, disappearance of all target lesions; PR = Partial Response, \>=30% decrease in the sum of the longest diameter of target lesions; PD = progressive disease, \>=20% increase in sum of target lesions and/or presence of new lesions and/or substantial increase in non-target lesion; SD = stable disease, response not meeting CR or PR or PD; ORR = overall response rate, defined as CR+PR

  From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months

• Part 3: Progression Free Survival (PFS)

  Progression Free Survival (PFS) was defined as the time from study treatment start date to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 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 and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm.

  From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months

Secondary Outcomes (33)

• Duration of Response (DoR)

  From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months

• Progression Free Survival (PFS)

  From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months

• Overall Survival (OS)

  From study treatment start date until date of of death from any cause, assessed up to approximately 90 months

• Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P)

  Day 1, Day 15, Week 8, Week 12, Week 16, Week 20

• Cmax of Trametinib in the Triple Combination (D+T+P)

  Day 1, Day 15, Week 8, Week 12, Week 16, Week 20

Study Arms (9)

Part 1: Dabrafenib and Panitumumab

EXPERIMENTAL

In Part 1 subjects will be assigned to escalation cohort of the doublet of dabrafenib and panitumumab based on the monotherapy doses of dabrafenib (150 milligrams \[mg\] twice daily) and panitumumab (6 milligrams per kilogram \[mg/kg\] every-2-week \[Q2W\]). Dose escalation will follow a 3+3 dose escalation procedure. If the initial combination dose of dabrafenib and panitumumab in Cohort 1 (starting dose) is not tolerable, lower dose combination(s) may be evaluated.

Drug: Dabrafenib; Drug: Panitumumab

Part 1: Dabrafenib, Trametinib and Panitumumab

EXPERIMENTAL

In Part 1 after the dabrafenib/panitumumab combination dose is defined, subsequent cohorts will evaluate the addition of trametinib based on a panitumumab dose that is one dose level lower than the dabrafenib/panitumumab dose defined in Cohort 1. Trametinib starting at 1.5 mg once daily will be added to the combination of dabrafenib and panitumumab. Dose escalation will follow a 3+3 dose escalation procedure until the full monotherapy doses of all agents are evaluated or the maximum tolerated dose is determined.

Drug: Dabrafenib; Drug: Trametinib; Drug: Panitumumab

Part 2: Dabrafenib and panitumumab

EXPERIMENTAL

In Part 2, subjects will be assigned to expansion cohorts at a selected dose of dabrafenib in combination with panitumumab

Drug: Dabrafenib; Drug: Panitumumab

Part 2: Dabrafenib, Trametinib and Panitumumab

EXPERIMENTAL

In Part 2, subjects will be assigned to expansion cohorts at selected dose of trametinib plus dabrafenib in combination with panitumumab.

Drug: Dabrafenib; Drug: Trametinib; Drug: Panitumumab

Part 4a: Trametinib and Panitumumab

EXPERIMENTAL

Subject will be administered starting dose of Trametinib 2 mg once daily and Panitumumab 6mg/kg Q2W. If the initial combination dose of trametinib and panitumumab in Cohort 1 (starting dose) is not tolerable, the lower dose combination defined in de-escalation cohorts (Cohort -1A, -1B and/or -1C) may be evaluated. Cohort -1A: Trametinib 1.5 mg once daily and Panitumumab 6 mg/kg Q2W; Cohort -1B: Trametinib 2 mg once daily and Panitumumab 4.8 mg/kg Q2W; Cohort-1C: Trametinib 1.5 mg once daily and Panitumumab 4.8 mg/kg Q2W

Drug: Trametinib; Drug: Panitumumab

Part 4b: Trametinib and Panitumumab

EXPERIMENTAL

In Part 4B cohort expansion, subjects will be assigned to expansion cohorts at a selected dose of trametinib in combination with panitumumab. Enrollment in expansion cohorts will be initiated once dose escalation for the trametinib /panitumumab combination has been completed. Subjects with advanced/metastatic CRC with either a BRAF-mutation (Cohort 1E) or who developed secondary resistance to prior anti-EGFR therapy (Cohort 2E).

Drug: Trametinib; Drug: Panitumumab

Part 3a: Dabrafenib and Panitumumab

EXPERIMENTAL

Subjects will be randomized to receive dabrafenib plus panitumumab. Dose levels for dabrafenib, and panitumumab in Part 3 will be chosen based on emerging PK, PD, and tolerability data from Part 1 and Part 2.

Drug: Dabrafenib; Drug: Panitumumab

Part 3b: Dabrafenib, Trametinib and Panitumumab

EXPERIMENTAL

Subjects will be randomized to receive study treatment as dabrafenib plus trametinib plus panitumumab. Dose levels for dabrafenib, trametinib and panitumumab in Part 3 will be chosen based on emerging PK, PD, and tolerability data from Part 1 and Part 2.

Drug: Dabrafenib; Drug: Trametinib

Part 3c: Chemotherapy comparator

EXPERIMENTAL

Subjects will be randomized to receive chemotherapy comparator. The chemotherapy comparator will consist of a standard chemotherapy regimen with or without the addition of a biological agent, based on local practice preferences. The available chemotherapy regimens includes 5-fluorouracil-based chemotherapy

Device: 5-fluorouracil

Interventions

Dabrafenib DRUG

Each capsule contains 50 mg or 75 mg of GSK2118436; 50 mg strength capsules are Swedish orange (dark red) opaque hypromellose size 2 capsules and 75 mg strength capsules are pink opaque hypromellose size 1 capsules. The initial dosing regimen will be twice daily (BID) continuous oral daily dosing.

Also known as: GSK2118436, DRB436

Part 1: Dabrafenib and Panitumumab; Part 1: Dabrafenib, Trametinib and Panitumumab; Part 2: Dabrafenib and panitumumab; Part 2: Dabrafenib, Trametinib and Panitumumab; Part 3a: Dabrafenib and Panitumumab; Part 3b: Dabrafenib, Trametinib and Panitumumab

Trametinib DRUG

Each tablet contains 0.5mg or 2.0 mg GSK1120212; 0.5 mg is yellow modified oval biconvex film-coated tablets of size 4.8 mm X 8.9 mm and 2 mg as pink round biconvex film coated tablets;7.5 mm in diameter. The initial dosing regimen will be once daily continuous oral daily dosing.

Also known as: GSK1120212, TMT212

Part 1: Dabrafenib, Trametinib and Panitumumab; Part 2: Dabrafenib, Trametinib and Panitumumab; Part 3b: Dabrafenib, Trametinib and Panitumumab; Part 4a: Trametinib and Panitumumab; Part 4b: Trametinib and Panitumumab

Panitumumab DRUG

Panitumumab is a sterile, colorless, translucent-to-white amorphous, proteinaceous powder available as 100 mg panitumumab in 5 mL (20 mg/mL) single-use vial; 200 mg panitumumab in 10 mL (20 mg/mL) single-use vial; 400 mg panitumumab in 20 mL (20 mg/mL) single-use vial; to be administered as an intravenous infusion over 60 minutes, every 14 days. Doses higher than 1000 mg should be administered over 90 minutes.

Part 1: Dabrafenib and Panitumumab; Part 1: Dabrafenib, Trametinib and Panitumumab; Part 2: Dabrafenib and panitumumab; Part 2: Dabrafenib, Trametinib and Panitumumab; Part 3a: Dabrafenib and Panitumumab; Part 4a: Trametinib and Panitumumab; Part 4b: Trametinib and Panitumumab

5-fluorouracil DEVICE

5-fluorouracil-based chemotherapy

Part 3c: Chemotherapy comparator

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provided written informed consent,
• Male or female \>=18 years of age and able to swallow and retain orally administered study treatment and does not have any clinically significant gastrointestinal (GI) abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach and/or bowels.
• Part 1 and Part 2: Histologically- or cytologically-confirmed diagnosis of advanced or metastatic BRAF V600E mutation positive CRC
• Part 4A and 4B ONLY: Histologically- or cytologically-confirmed diagnosis of advanced or metastatic CRC that either harbours the BRAF V600E -mutation, as determined by relevant genetic testing OR has developed secondary resistance to anti-EGFR therapy, defined as patients that derived benefit (disease control based on investigator assessment for \>6 months OR partial response \[confirmed or unconfirmed\] based on RECIST 1.1) from prior anti-EGFR-containing therapy (as defined below) and then subsequently progressed on therapy. The anti-EGFR therapy must have been the most recent therapy and the patient must have progressed based on investigator assessment within 3 months of screening. Acceptable prior anti-EGFR-containing therapies include: a. Monotherapy anti-EGFR, including cetuximab or panitumumab OR b. irinotecan/anti-EGFR combo after previously having disease progression (based on investigator assessment) on an irinotecan-containing regimen
• Part 3: Histologically- or cytologically-confirmed diagnosis of BRAFV600E mutation positive advanced or metastatic colorectal cancer (CRC who are eligible to receive fluoropyrimidine-containing chemotherapy regimen that have experienced documented radiographic progression on one prior line of fluoropyrimidine-containing chemotherapy (previous anti-EGFR therapy is excluded), Second-line for advanced/metastatic disease, having failed or been intolerant to at least one regimen of fluoropyrimidine-containing chemotherapy including irinotecan or oxaliplatin in the advanced/metastatic setting. Enrollment in Part 3 may only occur following confirmation of KRAS wild-type cancer.
• Archival tissue is required; if archival tissue is not available or found to not contain tumor tissue, a fresh biopsy is required.
• Measurable disease per RECIST version 1.1.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use one of the contraception methods listed in protocol.
• Female subjects are eligible if: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or post-menopausal female defined as 12 months of spontaneous amenorrhea to be verified with a follicle-stimulating hormone (FSH) level \>40 Milli-international units per milliliter (MIU/mL) and estradiol level \<40 picogram per milliliter (pg/mL). Child-bearing potential and agrees to use one of the contraceptive methods listed in protocol.
• Female subjects must agree to use contraception from 7 days prior to the first dose of study drug(s) until 6 months after the last dose of panitumumab, until 4 months after the last dose of trametinib, or 4 weeks after the last dose of dabrafenib, whichever is longer. Additionally, women of childbearing potential must have had a negative serum pregnancy test within 7 days prior to the first dose of study drug(s).
• Adequate organ system function as defined in absolute neutrophil count greater than or equal to 1.2X10\^9/Liter (L), hemoglobin greater than or equal to 9 grams per deciliter (g/dL) or 5.6 millimoles per litre (mmol/L), platelets greater than or equal to 75 × 10\^9/L, Prothrombin Time / International Normalized Ratio (PT/INR) and Partial Thromboplastin Time (PTT) less than or equal to 1.5X upper limit of normal (ULN); serum magnesium greater than or equal to the lower limit of normal (LLN); albumin greater than or equal to 2.5 g/dL or 25 grams per liter (g/L), total bilirubin less than or equal to 1.5XULN, and Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) less than or equal to 2.5X ULN; creatinine less than or equal to 1.5XULN or calculated creatinine clearance greater than or equal to 50mL/min; left ventricular ejection fraction (LVEF) greater than or equal to the LLN by echocardiography (ECHO) or multigated acquisition scan (MUGA).

You may not qualify if:

• History of prior malignancy, other than colorectal cancer.
• Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures.
• Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease per investigator's assessment).
• History of sensitivity to heparin or heparin-induced thrombocytopenia.
• Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy or biologic therapy).
• Prior exposure to a MEK inhibitor.
• Part 1, Part 2 and BRAF-mutant patients in Part 4 ONLY: Prior exposure to a BRAF inhibitor.
• Part 1, Part 2 and BRAF-mutant patients in Part 4 ONLY: Known presence of KRAS-mutation based on previous KRAS-testing. Note: Prospective KRAS testing is not required. However, if the results of previous KRAS testing are known, they must be used in assessing eligibility. KRAS testing will be performed retrospectively for all patients.
• Part 3: Prior exposure to EGFR inhibitors or an anti-EGFR antibody
• Received an investigational or approved anti-cancer drug within 4 weeks, or within 5 half-lives (whichever is shorter) of the first dose of study drug(s). At least 14 days must have passed between the last dose of prior investigational agent and the first dose of study drug(s).
• Part 3: Received more than one prior anti-cancer therapy in the metastatic setting, exclusive of previous adjuvant regimens. Previous investigational anti-cancer therapy in the metastatic setting is prohibited.
• Current use of a prohibited medication or requirement to dose with any of these medications during treatment with study drug(s).
• Known Hepatitis B, or Hepatitis C infection.
• Any major surgery, radiotherapy or immunotherapy within the 4 weeks prior to first dose of study drug(s). Limited radiotherapy with in the 2 weeks prior to first dose of study drug(s).
• Chemotherapy regimens with delayed toxicity within the 3 weeks prior to first dose of study drug(s). Chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity within 2 weeks prior to first dose of study drug(s).

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (20)

Novartis Investigative Site

Scottsdale, Arizona, 85259, United States

Location

Novartis Investigative Site

San Francisco, California, 94115, United States

Location

Novartis Investigative Site

Boston, Massachusetts, 02114, United States

Location

Novartis Investigative Site

Boston, Massachusetts, 02215, United States

Location

Novartis Investigative Site

New York, New York, 10065, United States

Location

Novartis Investigative Site

Chapel Hill, North Carolina, 27599, United States

Location

Novartis Investigative Site

Philadelphia, Pennsylvania, 19104, United States

Location

Novartis Investigative Site

Nashville, Tennessee, 37203, United States

Location

Novartis Investigative Site

Brussels, 1200, Belgium

Location

Novartis Investigative Site

Leuven, 3000, Belgium

Location

Novartis Investigative Site

Paris, 75571, France

Location

Novartis Investigative Site

Villejuif, 94805, France

Location

Novartis Investigative Site

Candiolo, 10060, Italy

Location

Novartis Investigative Site

Milan, 20162, Italy

Location

Novartis Investigative Site

Aichi, 464-8681, Japan

Location

Novartis Investigative Site

Chiba, 277-8577, Japan

Location

Novartis Investigative Site

Amsterdam, 1066 CX, Netherlands

Location

Novartis Investigative Site

Utrecht, 3584 CX, Netherlands

Location

Novartis Investigative Site

Barcelona, 08035, Spain

Location

Novartis Investigative Site

Birmingham, B15 2TH, United Kingdom

Location

MeSH Terms

Conditions

Neoplasms; Colorectal Neoplasms

Interventions

dabrafenib; trametinib; Panitumumab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: The original intention of the study was to include a randomized phase 2 portion of the study as a "Part 3"; however, a preliminary analysis did not meet predetermined criteria for efficacy. As a result, Part 3 of the study was not initiated.

Study Record Dates

• First Submitted: December 6, 2012
• First Posted: December 17, 2012
• Study Start: December 19, 2012
• Primary Completion: June 18, 2020
• Study Completion: June 18, 2020
• Last Updated: October 29, 2021
• Results First Posted: October 29, 2021

Record last verified: 2021-09

Data Sharing

• IPD Sharing: Will share

Locations

IT (2); ES (1); JP (2); NL (2); BE (2); FR (2); GB (1); US (8)