Phase I Multi-Center Study of Hypofractionated Radiotherapy in Combination With Durvalumab and Tremelimumab in Patients With Recurrent/Metastatic Advanced Cervical, Vaginal, or Vulvar Cancer
Overview
- Phase
- Phase 1
- Intervention
- Not specified
- Conditions
- Advanced Cervical Adenocarcinoma
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 20
- Locations
- 2
- Primary Endpoint
- Incidence of adverse events by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.03
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
This phase I trial studies how well stereotactic body radiation therapy works in combination with tremelimumab and durvalumab in treating participants with cervical, vaginal, or vulvar cancers that have come back (recurrent) or spread to other areas of the body (metastatic). Stereotactic body radiation therapy is a specialized radiation therapy that sends x-rays directly to the tumor using smaller doses over several days and may cause less damage to normal tissue. Immunotherapy with monoclonal antibodies, such as tremelimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Durvalumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Giving stereotactic body radiation therapy, tremelimumab, and durvalumab may work better in treating participants with cervical, vaginal, or vulvar cancers.
Detailed Description
PRIMARY OBJECTIVE: I. To determine the safety, and tolerability of combined immune checkpoint blockade with 3 fractions of stereotactic body radiation therapy (stereotactic ablative radiotherapy \[SABR\]) of up to two metastatic lesions in patients with recurrent and or metastatic cervical, vaginal, or vulvar cancer. SECONDARY OBJECTIVES: I. To evaluate clinical response rates and assess toxicities of treatment to durvalumab combined with tremelimumab with 3 fractions of SABR of at least one and up to two metastatic lesions in patients with recurrent/metastatic cervical, vaginal, or vulvar cancer. II. To estimate progression-free survival, overall survival, and time to next treatment. EXPLORATORY OBJECTIVES: I. To evaluate potential biomarkers of immune response to combined immune-checkpoint inhibition with SABR and correlate this with clinical response to treatment. II. To evaluate potential biomarkers of immune response including cervical and rectal microbial diversity, cervical immune cell infiltration and peripheral immune cell activation as correlates of clinical response to treatment. OUTLINE: Participants receive tremelimumab intravenously (IV) over 1 hour followed by durvalumab IV over 1 hour on day 1 of each cycle. Participants also undergo SABR over 30-45 minutes on days 8, 10, and 12 of cycle 1. Treatment with tremelimumab repeats every 4 weeks for up to 4 cycles, and treatment with durvalumab repeats every 4 weeks for up to 8 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, participants are followed up at 30 days, at 2, 3, 4, 6, 8, 10, and 12 months, and then every 6 months thereafter.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Written informed consent obtained from subject prior to any protocol related procedures
- •Performance status Eastern Cooperative Oncology Group (ECOG) 0-
- •Body weight \> 30 kg
- •Must have an average life expectancy of 6 months
- •Patient is able and willing to comply with protocol and study procedures for the duration of the study including undergoing treatment and scheduled visits and examinations including follow-up visits
- •Histological diagnosis of recurrent or metastatic cervical, vaginal, or vulvar cancer or an unknown pelvic malignancy most likely to have arisen from these sites as determined clinically by the treating physicians (i.e. squamous cell carcinoma or adenocarcinoma that is high risk \[HR\] human papillomavirus positive \[HPV\]+, but not limited to this example)
- •Metastatic disease in at least two distinct lesions (including the index lesion to be treated) with at least one site outside of the radiation field and evaluable by Response Evaluation Criteria in Solid Tumors (RECIST) criteria for evaluation of response
- •At least one index lesion to be treated measuring 1 cm amenable to hypofractionated radiation therapy
- •Staging computed tomography (CT) scans done prior to enrollment
- •Have had at least one line of prior platinum-based systemic chemotherapy once diagnosed with recurrence or metastatic disease if primary cervical cancer. If a patient has primary vulvar or vaginal cancer, there is not a requirement.
Exclusion Criteria
- •Involvement in the planning and/or conduct of the study
- •Previous enrollment in the present study
- •Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab + tremelimumab combination therapy
- •Prior treatment with an anti-CTLA-4, including tremelimumab PD-1 or PD-L1 inhibitor, including durvalumab
- •Prior oncology vaccine therapy
- •Prior radiation treatment to the index lesion to be treated
- •Prior radiation which overlaps and precludes hypofractionated treatment to the index lesion
- •Treatment with other investigational agent within 4 weeks to the first dose of tremelimumab or durvalumab
- •Concomitant therapy with any of the following: interleukin-2 (IL-2), interferon, or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigational therapies; all such therapies must have been discontinued \> 4 weeks
- •Any unresolved toxicity (CTCAE grade \< 2) from previous anti-cancer therapy; (subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripherally neuropathy)
Outcomes
Primary Outcomes
Incidence of adverse events by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.03
Time Frame: Up to 3 months after last dose of durvalumab
Will be assessed based on dose limiting toxicities (DLTs) and based on adverse events (AEs) throughout the entire treatment period. In the overall assessment of adverse events, AEs will be tabulated by body system, type and grade, overall and by disease cohort. The number and percentage of patients experiencing at least one grade 3 or higher AE will also be reported.
Secondary Outcomes
- Overall Survival(From start of therapy to death from any cause, assessed up to 1 year)
- Time to next treatment (TTNT)(From the end of immune-checkpoint inhibition treatment to institution of next therapy, assessed up to 1 year)
- Response to treatment by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune-related response criteria(Up to 1 year)
- Progression-Free Survival(From the start of therapy up to first documented disease progression or death from any cause, assessed up to 1 year)