Phase I Trial Of Hypofractionated Radiotherapy In Combination With MEDI4736 And Tremelimumab For Patients With Metastatic Melanoma And Lung, Breast And Pancreatic Cancers
Overview
- Phase
- Phase 1
- Intervention
- Radiotherapy
- Conditions
- Metastatic
- Sponsor
- Abramson Cancer Center at Penn Medicine
- Enrollment
- 53
- Locations
- 1
- Primary Endpoint
- Number of Adverse Events
- Status
- Completed
- Last Updated
- 5 months ago
Overview
Brief Summary
The main purpose of this study is to determine how best to combine hypofractionated radiotherapy, MEDI4736, and tremelimumab and to determine how safe and tolerable hypofractionated radiotherapy, MEDI4736, and tremelimumab are when given together in subjects with metastatic, melanoma, non small cell lung cancer (NSCLC), breast cancer, and pancreatic cancer.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients with histologically or cytologically confirmed metastatic melanoma,metastatic non-small cell lung cancer, metastatic breast cancer, or metastatic pancreatic adenocarcinoma relapsed or refractory to therapy as outlined below or patients with these malignancies who have declined, are or have become unable to tolerate (e.g. progressive chemotherapy-associated peripheral neuropathy), or were not eligible for standard therapy: Metastatic melanoma patients at any line of therapy, Metastatic non-small cell lung cancer patients who have relapsed or are refractory to at least one line of systemic anti-cancer therapy for metastatic disease, including cytotoxic chemotherapy or targeted therapy, Metastatic breast cancer patients who have relapsed or are refractory to at least one line of systemic anti-cancer therapy for metastatic disease, such as cytotoxic chemotherapy, hormonal therapy, or targeted therapy, Metastatic pancreatic adenocarcinoma who have relapsed or are refractory to at least one line of systemic anti-cancer therapy for metastatic disease, such as cytotoxic chemotherapy or targeted therapy
- •At least two measurable lesions (including the index lesion) according to RECIST guidelines v1.1
- •An index lesion measuring between 1cm - 7cm that is amenable to hypofractionated radiation therapy at the discretion of the treating radiation oncologist
- •o Index lesions in the pancreas are excluded in the second cohort
- •Age greater than or equal to 18 years
- •Signed, written informed consent
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- •Adequate hematological function documented within 3 weeks prior to initial treatment based on: White blood cell ≥ 2,500 cells/ul without growth factor support, Absolute neutrophil count (ANC) ≥ 1,500 cells/ul without growth factor support, Hemoglobin ≥ 9 g/dL, Platelet count ≥ 100,000 platelets/ul, Adequate hepatic and renal function documented within 3 weeks prior to initial treatment based on: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN). For subjects with liver metastasis, ALT and AST ≤ 5 x ULN, Total bilirubin ≤1.5 x ULN except in patients with documented Gilbert's syndrome or liver metastasis, who must have a baseline total bilirubin ≤ 3.0 mg/dl, Serum creatinine ≤ 2.0 mg/dL
- •Full recovery from the acute effects of prior cancer treatments, defined as effects having resolved to NCI CTCAE v4.03 Grade 0 or 1 with the exception of alopecia and certain laboratory values as listed above. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by MEDI4736 and tremelimumab may be included (eg, hearing loss, neuropathy) upon approval of the PI.
- •For patients with central nervous system (CNS) metastases, metastases must be asymptomatic at the time of Day 1 of the study and meet the following criteria:
Exclusion Criteria
- •Concurrent enrollment in another clinical study, unless in a follow-up period or the study is an observational or non-interventional study
- •Prior treatment with anti-CTLA4, anti-PD-1, or anti-PD-L1 (approved or investigational agent)
- •Concurrent treatment with any anticancer agent, including chemotherapy, immunotherapy, or biologic therapy. In breast cancer patients, concurrent use of hormonal therapy (but not trastuzumab) is acceptable provided hormonal therapy was initiated more than 30 days prior to treatment on this study.
- •Treatment with any other investigational agent within 3 weeks prior to the first dose of DURVALUMAB (MEDI4736) and tremelimumab
- •Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
- •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 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 DURVALUMAB (MEDI4736) and tremelimumab or still recovering from prior surgery Note: Local surgery of isolated lesions for palliative intent is acceptable
- •Current or prior use of immunosuppressive medication within 14 days before the first dose of DURVALUMAB (MEDI4736) and tremelimumab with the exceptions of intranasal and inhaled corticosteroids, systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent, or steroids used transiently to control contrast agent allergies for radiographic studies.
- •History of allogenic organ transplantation.
Arms & Interventions
Cohort 1
Subjects will receive 20 mg/kg MEDI4736 and 1 mg/kg tremelimumab in combination every 4 weeks for 4 doses, followed by 10 mg/kg MEDI4736 monotherapy every 2 weeks for 18 doses. The total duration of therapy is 12 months. Cohort 1 tests 8 Gy x 3 fractions
Intervention: Radiotherapy
Cohort 1
Subjects will receive 20 mg/kg MEDI4736 and 1 mg/kg tremelimumab in combination every 4 weeks for 4 doses, followed by 10 mg/kg MEDI4736 monotherapy every 2 weeks for 18 doses. The total duration of therapy is 12 months. Cohort 1 tests 8 Gy x 3 fractions
Intervention: MEDI4736
Cohort 1
Subjects will receive 20 mg/kg MEDI4736 and 1 mg/kg tremelimumab in combination every 4 weeks for 4 doses, followed by 10 mg/kg MEDI4736 monotherapy every 2 weeks for 18 doses. The total duration of therapy is 12 months. Cohort 1 tests 8 Gy x 3 fractions
Intervention: Tremelimumab
Cohort 2
Subjects will receive 20 mg/kg MEDI4736 and 1 mg/kg tremelimumab in combination every 4 weeks for 4 doses, followed by 10 mg/kg MEDI4736 monotherapy every 2 weeks for 18 doses. The total duration of therapy is 12 months. Cohort 2 tests 17 Gy x 1 fraction.
Intervention: Radiotherapy
Cohort 2
Subjects will receive 20 mg/kg MEDI4736 and 1 mg/kg tremelimumab in combination every 4 weeks for 4 doses, followed by 10 mg/kg MEDI4736 monotherapy every 2 weeks for 18 doses. The total duration of therapy is 12 months. Cohort 2 tests 17 Gy x 1 fraction.
Intervention: MEDI4736
Cohort 2
Subjects will receive 20 mg/kg MEDI4736 and 1 mg/kg tremelimumab in combination every 4 weeks for 4 doses, followed by 10 mg/kg MEDI4736 monotherapy every 2 weeks for 18 doses. The total duration of therapy is 12 months. Cohort 2 tests 17 Gy x 1 fraction.
Intervention: Tremelimumab
Outcomes
Primary Outcomes
Number of Adverse Events
Time Frame: 12 months