Durvalumab and Tremelimumab Combination in Somatically Hypermutated Recurrent Solid Tumors

NCT03911557 | Completed Phase 2 DMC FDA Drug

• 1 other identifier: MCC-18-MULTI-25-PMC
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

This study will examine whether patients with relapsed/refractory solid tumors harboring evidence of somatic hypermutation (intermediate versus high tumor mutational burden) will exhibit improvement in disease progression-free survival with dual Tremelimumab and Durvalumab treatment.

Conditions

Tumor, Solid

Keywords

mutational burden; TMB; PD-1; CTLA-4; MEDI4736; durvalumab; tremelimumab; immune therapy; refractory

Outcome Measures

Primary Outcomes (1)

• Time-to-progression ratio (TTP)

  The TTP (time-to-progression) ratio is defined for individual patients as the ratio of their TTP on the current therapy to their TTP on the most recent previous therapy

  2 years (baseline to follow-up)

Secondary Outcomes (1)

• Progression-free survival

  2 years (baseline to follow-up)

Study Arms (1)

Patients with moderate to high tumor mutational burden

EXPERIMENTAL

Patients with recurrent or refractory disease in solid tumors naïve to anti-PD-1/PD-L1 or anti-CTLA-4 immunotherapy and have moderate to high tumor mutational burden (TMB)

Drug: Durvalumab and Tremelimumab

Interventions

Durvalumab and Tremelimumab DRUG

Durvalumab 1500mg + tremelimumab 75mg via IV infusion Q4W, starting on Week 1, for up to a maximum of 4 doses/cycles followed by durvalumab monotherapy 1500 mg via IV infusion Q4W, starting 4 weeks after the last infusion of the combination, for up to a maximum of 2 years of total therapy.

Patients with moderate to high tumor mutational burden

Eligibility Criteria

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

You may qualify if:

• Relapsed/refractory solid tumor patients not previously treated with anti-PD-1/PD-L1 or anti-CTLA-4 immunotherapy whose tumors expressed a high tumor mutational burden (TMB) (TMB high \>20 mutations/MB) or moderate TMB (10-20 mutations/MB) as based on next generation sequencing (NGS)
• Age \>18 years at time of study entry
• Eastern Cooperative Oncology Group (ECOG) performance status of at least 2 and life expectancy greater than 3 months
• Accurate documentation of date of starting previous therapy and date of progression to establish TTP from most recent therapy
• Patient must have normal organ and marrow function independent of transfusion for at least 7 days prior to screening and independent of growth factor support for at least 14 days prior to screening as defined below:
• Absolute neutrophil count (ANC ≥1.5 (or 1.0) x (\> 1500 per mm3)
• Platelet count ≥100 (or 75) x 109/L (\>75,000 per mm3)
• Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome, who will be allowed only in consultation with their physician.
• AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN
• Measured creatinine clearance (CL) \>40 mL/min or Calculated creatinine clearance CL\>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance
• The effects of MEDI4736 and tremelimumab on the developing human fetus are unknown. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. 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 ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)
• Females of childbearing potential who are sexually active with a non-sterilized male partner must use at least 1 highly effective method of contraception from the time of screening and must agree to continue using such precaution for 180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose of durvalumab monotherapy. Non-sterilized male partners of female patient must use male condom plus spermicide throughout this period. Cessation of birth control after this point should be discussed with a responsible physician. Not engaging in sexual activity for the total duration of the drug treatment and the drug washout period is an acceptable practice; however, periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Female patients should also refrain from breastfeeding throughout this period.
• Non-sterilized males who are sexually active with a female partner of childbearing potential must use a male condom plus spermicide from screening through 180 days after receipt of the final dose of durvalumab + tremelimumab combination therapy or 90 days after receipt of the final dose of durvalumab monotherapy. Not engaging in sexual activity is an acceptable practice; however, occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Male patients should refrain from sperm donation throughout this period

You may not qualify if:

• Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapeutic agent, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies) 30 days prior to the first dose of study drug
• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Physician
• Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of the IP (investigational product, in this study, specifically durvalumab + tremelimumab combination). Note: Local surgery of isolated lesions for palliative intent is acceptable
• History of allogenic organ transplantation
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc\]). The following are exceptions to this criterion:
• Patients with vitiligo or alopecia
• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
• Any chronic skin condition that does not require systemic therapy
• Patients without active disease in the last 5 years may be included but only after consultation with the study physician
• Patients with celiac disease controlled by diet alone
• Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, 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 requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
• History of another primary malignancy except for
• Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of the IP ( durvalumab + tremelimumab combination ) and of low potential risk for recurrence
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease

Sponsors & Collaborators

• John L. Villano, MD, PhD: lead

Study Sites (1)

Markey Cancer Center

Lexington, Kentucky, 40536, United States

Location

MeSH Terms

Conditions

Neoplasms; Diabetes Mellitus, Insulin-Dependent, 12

Interventions

durvalumab; tremelimumab

Study Officials

• John Villano, MD

  University of Kentucky

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: April 9, 2019
• First Posted: April 11, 2019
• Study Start: June 8, 2019
• Primary Completion: October 10, 2025
• Study Completion: October 10, 2025
• Last Updated: November 12, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)