Dabrafenib + Trametinib + PDR001 In Colorectal Cancer

NCT03668431 | Unknown Phase 2 DMC FDA Drug

• 1 other identifier: 18-144
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 2

Brief Summary

This research study is studying a combination of drugs as a possible treatment for metastatic colorectal cancer characterized by BRAF V600E mutation. The names of the study drugs involved in this study are:

• Dabrafenib
• Trametinib
• PDR001

Conditions

Metastatic Colorectal Cancer

Keywords

Metastatic colorectal cancer

Outcome Measures

Primary Outcomes (2)

• Overall Response Rate

  The participants best overall response will be assessed using RECIST 1.1 criteria * Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. * Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. * Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). * Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

  From the start of the treatment until disease progression/recurrence, up to approximately 5 years

• Number of participants with grade 3, 4 and 5 adverse events

  Adverse Events will be assessed using Common Terminology Criteria for Adverse Events (CTCAE 4)

  From the start of treatment until 30 days after the last dose of a study drug, up to approximately 5 years

Secondary Outcomes (5)

• Progression Free Survival

  From the date of randomization until disease progression or death due to any cause, up to approximately 5 years

• Disease Control Rate

  From the start of the treatment until disease progression/recurrence, up to approximately 5 years

• Duration of Response

  From the first documented response until the time of disease progression, up to approximately 5 years

• Overall Survival

  From the date of randomization until the time of death, up to approximately 10 years

• Mechanisms of response and resistance to dabrafenib, trametinib, and PDR001

  Pre treatment and day 15

Study Arms (1)

PDR001, Dabrafenib, Trametinib

EXPERIMENTAL

Patients who fulfill eligibility criteria will be entered into the trial to receive PDR001, Dabrafenib, Trametinib. Treatment will be administered on an outpatient basis. After the screening procedures confirm participation in the research study: * Dabrafenib will be taken twice a day for 28 consecutive days * Trametinib will be taken once a day for 28 consecutive days * PDR001 will be administered IV every 28 days.

Drug: Dabrafenib; Drug: Trametinib; Drug: PDR001

Interventions

Dabrafenib DRUG

Dabrafenib will be taken twice a day for 28 consecutive days .

Also known as: Tafinlar®

PDR001, Dabrafenib, Trametinib

Trametinib DRUG

Trametinib will be taken once a day for 28 consecutive days

Also known as: Mekinist®

PDR001, Dabrafenib, Trametinib

PDR001 DRUG

PDR001 will be administered IV every 28 days

PDR001, Dabrafenib, Trametinib

Eligibility Criteria

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

You may qualify if:

• Participants must have histologically or cytologically confirmed metastatic colorectal cancer and a documented BRAF V600E mutation by a CLIA-certified laboratory test and must be wild-type for KRAS and NRAS.
• Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional techniques or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam. See Section 11 for the evaluation of measurable disease.
• Patients may have received prior chemotherapy, prior anti-EGFR therapy, prior BRAF or MEK inhibitor, or prior immunotherapy (e.g. anti-PD1/PD-L1). Patients will also be allowed without prior treatments. If patient has been treated in the past, they must be at least 4 weeks since prior chemotherapy or radiation therapy.
• Age ≥ 18 years
• ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
• Life expectancy of greater than 3 months
• Participants must have normal organ and marrow function as defined below:
• leukocytes ≥3,000/mcL
• absolute neutrophil count ≥1,500/mcL
• platelets ≥100,000/mcL
• total bilirubin within normal institutional limits
• AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal
• creatinine within normal institutional limits --- OR
• creatinine clearance ≥ 60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal.
• PT/INR \<1.5 x ULN and PTT \<1.5 ULN

You may not qualify if:

• Participants who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
• Participants who are receiving any other investigational agents.
• Participants with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to of trametinib, dabrafenib or PDR001.
• Participants receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 are ineligible but once on treatment must be used with caution. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians' Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant women are excluded from this study because trametinib, dabrafenib or PDR001 have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with trametinib, dabrafenib or PDR001 breastfeeding should be discontinued if the mother is treated with trametinib, dabrafenib or PDR001.
• HIV-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with trametinib, dabrafenib or PDR001. In addition, these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.
• Active known or suspected autoimmune disease or a documented history of autoimmune disease, including ulcerative colitis and Crohn's disease (Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll).
• Systemic chronic steroid therapy (≥ 10mg/day prednisone or equivalent) or any immunosuppressive therapy 7 days prior to planned date for first dose of study treatment. Topical, inhaled, nasal and ophthalmic steroids are allowed.
• Current pneumonitis or interstitial lung disease.
• History of organ transplant requiring use of immunosuppressive medication.
• Taken an investigational drug ≤ 28 days or ≤ 5 half-lives (minimum 14 days) prior to start of study treatment, whichever is shorter.
• Current use of a prohibited medication.
• Active infection requiring systemic antibiotic therapy within 2 weeks prior to start of study treatment.

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• Novartis: collaborator
• Stand Up To Cancer: collaborator

Study Sites (2)

Massachusetts General Hosital Cancer Center

Boston, Massachusetts, 02114, United States

RECRUITING

Dana Farber Cancer Institite

Boston, Massachusetts, 02215, United States

RECRUITING

Related Publications (1)

• Tian J, Chen JH, Chao SX, Pelka K, Giannakis M, Hess J, Burke K, Jorgji V, Sindurakar P, Braverman J, Mehta A, Oka T, Huang M, Lieb D, Spurrell M, Allen JN, Abrams TA, Clark JW, Enzinger AC, Enzinger PC, Klempner SJ, McCleary NJ, Meyerhardt JA, Ryan DP, Yurgelun MB, Kanter K, Van Seventer EE, Baiev I, Chi G, Jarnagin J, Bradford WB, Wong E, Michel AG, Fetter IJ, Siravegna G, Gemma AJ, Sharpe A, Demehri S, Leary R, Campbell CD, Yilmaz O, Getz GA, Parikh AR, Hacohen N, Corcoran RB. Combined PD-1, BRAF and MEK inhibition in BRAFV600E colorectal cancer: a phase 2 trial. Nat Med. 2023 Feb;29(2):458-466. doi: 10.1038/s41591-022-02181-8. Epub 2023 Jan 26.

  PMID: 36702949 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

dabrafenib; trametinib; spartalizumab

Condition Hierarchy (Ancestors)

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

Study Officials

• Ryan Corcoran, MD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ryan Corcoran, MD

CONTACT

(617) 724-4000; rbcorcoran@partners.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: September 11, 2018
• First Posted: September 12, 2018
• Study Start: October 15, 2018
• Primary Completion: September 1, 2022
• Study Completion: December 1, 2022
• Last Updated: June 27, 2022

Record last verified: 2022-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)