Study of Durvalumab (MEDI4736) (Anti-PD-L1) and Trametinib (MEKi) in MSS Metastatic Colon Cancer

NCT03428126 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 2017-0514NCI-2018-00911
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical research study is to learn if durvalumab and trametinib can help to control microsatellite stable (MSS) colorectal cancer. The safety of these drugs will also be studied. This is an investigational study. Durvalumab is FDA approved and commercially available for the treatment of previously treated advanced bladder cancer. Trametinib is FDA approved in combination with another drug called dabrafenib for the treatment of unresectable or metastatic melanoma with BRAF V600E or BRAF V600K. It is investigational to use durvalumab and trametinib to treat MSS colorectal cancer. Up to 56 participants will be enrolled in this study. All will take part at MD Anderson.

Conditions

Malignant Neoplasms of Digestive Organs; Colorectal Cancer; Colon Cancer

Keywords

Malignant neoplasms of digestive organs; Colorectal Cancer; Colon Cancer; Durvalumab; MEDI4736; Trametinib; GSK1120212

Outcome Measures

Primary Outcomes (1)

• Immune-related Best Overall Response Rate.

  Best overall response rate (CR+PR) by immune-related response rate.

  From Baseline to 2 years

Secondary Outcomes (3)

• Progression Free Survival as Determined by irRC

  From Baseline to up to 2 years

• Overall Survival

  From Baseline to 2 years

• Disease Control Rate

  From Baseline to 2 years.

Study Arms (1)

Durvalumab + Trametinib

EXPERIMENTAL

Participants take Trametinib tablets by mouth every day. Trametinib taken alone for the first 7 days of the study then participants begin receiving it in combination with Durvalumab. Participants receive Durvalumab by vein every 4 weeks. Each cycle is 28 days.

Drug: Durvalumab; Drug: Trametinib

Interventions

Durvalumab DRUG

Dose Escalation and Dose Expansion Dose: 1500 mg by vein every 4 weeks in a 28 day cycle.

Also known as: MEDI4736

Durvalumab + Trametinib

Trametinib DRUG

Dose Escalation Starting Dose: 2mg by mouth daily in a 28 day cycle. Dose Expansion Dose: MTD from Dose Escalation.

Also known as: GSK1120212

Durvalumab + Trametinib

Eligibility Criteria

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

You may qualify if:

• Patients must have histologically or cytologically confirmed metastatic colorectal cancer.
• Patients must have measurable disease per RECIST v1.1 criteria.
• Patients must have had at least prior treatment with a fluoropyrimidine and either oxaliplatin or irinotecan.
• Age \>/=18 years. Because no dosing or adverse event data are currently available on the use of this combination in patients \<18 years of age, children are excluded from this study.
• Body weight \> 30kg.
• Life expectancy of greater than 6 months.
• ECOG performance status 0-1 (Karnofsky \>/=70%).
• Patients must have normal organ and marrow function as defined below: - Leukocytes \>/=3,000/mcL, Absolute neutrophil count \>/=1,500/mcL, Hemoglobin \>/=9.0g/dL, Platelets \>/=75,000/mcL, Total bilirubin \< 1.5 X institutional normal limits (subjects with known Gilbert syndrome are eligible with total bilirubin \< 3.0 mg/dL), AST(SGOT)/ALT(SGPT) \</=2.5 X institutional ULN (\</= 5 if liver metastases present), Creatinine within normal institutional limits OR, Creatinine clearance \> 40mL/min by Cockcroft-Gault or 24h urine collection.
• Known MSS status by either IHC or PCR. Known or evaluable BRAF and KRAS status.
• Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal subjects. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: -- Women \<50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately and will be removed from the study.
• Ability to understand and the willingness to sign a written informed consent document.
• Willingness to have 2 tumor biopsies; the first before and the second while on therapy (optional for all patients and may become mandatory in order to ensure 15 patients at MTD have paired biopsies).

You may not qualify if:

• Patients who have had chemotherapy within 2 weeks prior to first dose of study drug.
• Patients may not be receiving any other investigational agents.
• Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of study medication. Note: Local surgery of isolated lesions for palliative intent is acceptable.
• Patients with known brain metastases or leptomeningeal carcinomatosis will be excluded from this clinical trial. Patients with suspected brain metastases at screening should have an MRI (preferred) or CT each preferably with IV contrast of the brain prior to study entry.
• Mean QT interval corrected for heart rate (QTc) \>/= 470 ms calculated from 3 electrocardiograms (ECGs) using Fridericia's Correction.
• History of pneumonitis or interstitial lung disease (ILD).
• History of allogenic organ transplantation.
• Subjects with active, known, or suspected autoimmune disease including patients with a history of inflammatory bowel disease (ulcerative colitis or Crohn's disease); patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic sclerosis \[scleroderma\], systemic lupus erythematosus, autoimmune vasculitis (e.g., Wegener's granulomatosis), and central nervous system or motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome, myasthenia gravis, multiple sclerosis). Subjects with vitiligo, type I diabetes mellitus, Grave's disease, Hashimoto thyroiditis, psoriasis, and other mild autoimmune disease not requiring systemic treatment are permitted to enroll at the discretion of the investigator.
• Subjects with a condition requiring systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Subjects, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
• Prior exposure to T cell checkpoint inhibitor therapies.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirements, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
• History of active primary immunodeficiency.
• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice for patients suspected of having active infection), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible. Subjects positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
• Female subjects who are pregnant or breastfeeding or male or female subjects of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of study medications.

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• MedImmune LLC: collaborator
• AstraZeneca: collaborator
• Novartis: collaborator

Study Sites (1)

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Johnson B, Haymaker CL, Parra ER, Soto LMS, Wang X, Thomas JV, Dasari A, Morris VK, Raghav K, Vilar E, Kee BK, Eng C, Parseghian CM, Wolff RA, Lee Y, Lorenzini D, Laberiano-Fernandez C, Verma A, Lang W, Wistuba II, Futreal A, Kopetz S, Overman MJ. Phase II study of durvalumab (anti-PD-L1) and trametinib (MEKi) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC). J Immunother Cancer. 2022 Aug;10(8):e005332. doi: 10.1136/jitc-2022-005332.

  PMID: 36007963 DERIVED

Related Links

• University of Texas MD Anderson Cancer Center Website

MeSH Terms

Conditions

Colorectal Neoplasms; Colonic Neoplasms

Interventions

durvalumab; trametinib

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

Results Point of Contact

• Title: Dr. Michael Overman
• Organization: MD Anderson Cancer Center

moverman@mdanderson.org

(713) 792-2828

Study Officials

• Michael Overman, MD

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 5, 2018
• First Posted: February 9, 2018
• Study Start: March 21, 2018
• Primary Completion: May 5, 2022
• Study Completion: May 5, 2022
• Last Updated: June 15, 2023
• Results First Posted: June 15, 2023

Record last verified: 2023-06

Locations

US (1)