Comprehensive Stereotactic Body Radiotherapy (SBRT) to All Sites of Oligometastatic Non-small Cell Lung Cancer (NSCLC) Combined With Durvalumab (MEDI4736) and Tremelimumab Dual Immune Checkpoint Inhibition.
Overview
- Phase
- Phase 1
- Intervention
- Durvalumab
- Conditions
- Non-small Cell Lung Cancer
- Sponsor
- University of Wisconsin, Madison
- Enrollment
- 17
- Locations
- 1
- Primary Endpoint
- Safety and tolerability of SBRT followed by combined durvalumab and tremelimumab, assessed by CTCAE v4.03
- Status
- Terminated
- Last Updated
- 2 years ago
Overview
Brief Summary
This is a phase Ib study to evaluate safety and tolerability of dual checkpoint inhibition (DCI) of durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4) with SBRT in the treatment of oligometastatic NSCLC. This study will examine the sequential delivery of SBRT to all disease sites followed by combination of durvalumab and tremelimumab for patients for whom the goal is ablating all known sites of disease. The investigators anticipate that for many participants this will be the first line-therapy. Participants who have received prior-platinum-based chemotherapy and/or any line of prior chemotherapy are eligible. Prior immunotherapy treatment is not allowed.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Participants with histologically or cytologically confirmed stage IV NSCLC not amenable to curative surgery or radiation
- •Participants may have had prior chemotherapy or be chemotherapy naïve
- •Participants must have tumors that lack sensitizing EGFR mutation (e.g. exon 19 deletion or exon 21 L858R) or ALK rearrangement. If a participant has squamous histology, then EGFR and ALK testing is not required.
- •No prior treatment with cancer immunotherapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2 anti- (PD-L2) antibodies, excluding therapeutic anticancer vaccines.
- •Participants will have 6 or less extracranial sites, which can safely receive SBRT between 30 - 50 Gy in 5 fractions. A site may have multiple tumor lesions within it as long as the gross tumor volume (GTV) of the site is 8 cm or less and can be covered in an acceptable SBRT field determined by the PI. All gross disease must be amenable to treatment with SBRT, as allowable per normal tissue constraints. Participants will not have had any prior radiation therapy significantly overlapping a tumor site to be treated.
- •Participants must have evaluable disease, as defined by RECIST 1.
- •World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrollment
- •Life expectancy of \> 12 weeks
- •Participant is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
- •Participants with treated metastatic lesions to the brain may be enrolled after completing stereotactic radiosurgery (may enroll 14 days after treatment) or whole brain radiation (may enroll 14 days after treatment) and must be off corticosteroids for 14 days prior to start of SBRT.
Exclusion Criteria
- •Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
- •Previous enrollment in the present study
- •Mixed small-cell lung cancer and sarcomatoid variant NSCLC histology
- •Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable.
- •Major surgical procedure (as defined by the Investigator) within 14 days prior to the start of study treatment.
- •Participants with untreated spinal cord compression. Participants with spinal cord compression may be enrolled if stable after completing surgery (may enroll 14 days after surgery) or radiation (may enroll 14 days after radiation) and must be off corticosteroids for at least 14 days prior to the start of SBRT.
- •Participants with untreated brain metastasis. Participants with metastatic lesions to the brain may be enrolled after completing stereotactic radiosurgery or whole brain radiation (may enroll 14 days after radiation and must be off corticosteroids for at least 14 days prior to the start of SBRT.
- •Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an anti-CTLA4 inhibitor including tremelimumab
- •Participants with a known targetable EGFR mutation or ALK rearrangement
- •History of another primary malignancy except for:
Arms & Interventions
SBRT followed by Durvalumab+Tremelimumab
Therapeutic Interventions Stereotactic Body Radiotherapy (SBRT) to all sites of disease between 30 and 50 Gy in five fractions administered over two weeks. Investigational Product(s), Dose, and Mode of Administration: to begin 7 days (+/- 3 days) after radiation Durvalumab 1500 mg via infusion Q4W (equivalent to 20 mg/kg Q4W) until disease progression in patients \> 30 kg Tremelimumab 300 mg via infusion (equivalent to 4 mg/kg) in one dose in patients \>30 kg Weight-based dosing should be utilized for patients ≤30 kg; durvalumab 20 mg/kg Q4W and tremelimumab 4 mg/kg
Intervention: Durvalumab
SBRT followed by Durvalumab+Tremelimumab
Therapeutic Interventions Stereotactic Body Radiotherapy (SBRT) to all sites of disease between 30 and 50 Gy in five fractions administered over two weeks. Investigational Product(s), Dose, and Mode of Administration: to begin 7 days (+/- 3 days) after radiation Durvalumab 1500 mg via infusion Q4W (equivalent to 20 mg/kg Q4W) until disease progression in patients \> 30 kg Tremelimumab 300 mg via infusion (equivalent to 4 mg/kg) in one dose in patients \>30 kg Weight-based dosing should be utilized for patients ≤30 kg; durvalumab 20 mg/kg Q4W and tremelimumab 4 mg/kg
Intervention: Tremelimumab
SBRT followed by Durvalumab+Tremelimumab
Therapeutic Interventions Stereotactic Body Radiotherapy (SBRT) to all sites of disease between 30 and 50 Gy in five fractions administered over two weeks. Investigational Product(s), Dose, and Mode of Administration: to begin 7 days (+/- 3 days) after radiation Durvalumab 1500 mg via infusion Q4W (equivalent to 20 mg/kg Q4W) until disease progression in patients \> 30 kg Tremelimumab 300 mg via infusion (equivalent to 4 mg/kg) in one dose in patients \>30 kg Weight-based dosing should be utilized for patients ≤30 kg; durvalumab 20 mg/kg Q4W and tremelimumab 4 mg/kg
Intervention: Stereotactic Body Radiotherapy
Outcomes
Primary Outcomes
Safety and tolerability of SBRT followed by combined durvalumab and tremelimumab, assessed by CTCAE v4.03
Time Frame: Up to 3 years
Toxicities will be summarized by type and severity in tabular format. Toxicity rates (grade 2, grade 3, grade 4, grade ≥ 2, grade ≥ 3, etc.) will be calculated and reported along the corresponding 95% confidence intervals. The 95% confidence intervals will be constructed using the Wilson score method.
Secondary Outcomes
- Overall Survival assessed with RECIST 1.1 tumor assessments(Up to 4 years)
- Progression Free Survival assessed with RECIST 1.1 tumor assessments(Up to 4 years)