Phase Ib Study of Stereotactic Body Radiotherapy (SBRT) in Oligometastatic Non-small Lung Cancer (NSCLC) With Dual Immune Checkpoint Inhibition

NCT03275597 | Terminated Phase 1 FDA Drug

• 6 other identifiers: UW17003A533300SMPH\HUMAN ONCOLOGY\HUMAN ONCONCI-2017-01952Protocol Version 10/2//20202017-0665
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

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.

Conditions

Non-small Cell Lung Cancer; Non-small Cell Lung Cancer Stage IV

Outcome Measures

Primary Outcomes (1)

• Safety and tolerability of SBRT followed by combined durvalumab and tremelimumab, assessed by CTCAE v4.03

  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.

  Up to 3 years

Secondary Outcomes (2)

• Progression Free Survival assessed with RECIST 1.1 tumor assessments

  Up to 4 years

• Overall Survival assessed with RECIST 1.1 tumor assessments

  Up to 4 years

Other Outcomes (2)

• Evaluate immune response

  Up to 4 years

• Evaluate PD-L1 expression

  Up to 4 years

Study Arms (1)

SBRT followed by Durvalumab+Tremelimumab

EXPERIMENTAL

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

Drug: Durvalumab; Drug: Tremelimumab; Radiation: Stereotactic Body Radiotherapy

Interventions

Durvalumab DRUG

Durvalumab is an FDA-approved immunotherapy for cancer. Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa subclass that inhibits binding of PD-L1 and is being developed by AstraZeneca/MedImmune for use in the treatment of cancer.

Also known as: 1428935-60-7, D10808

SBRT followed by Durvalumab+Tremelimumab

Tremelimumab DRUG

Tremelimumab is a monoclonal antibody against CTLA-4. It is an IgG 2 kappa isotype mAb directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) also known as CD152 (cluster of differentiation 152). This is an immunomodulatory therapy (IMT) that is being developed by AstraZeneca for use in the treatment of cancer.

Also known as: 745013-59-6, QEN1X95CIX

SBRT followed by Durvalumab+Tremelimumab

Stereotactic Body Radiotherapy RADIATION

SBRT is a highly conformal approach to the delivery of radiation therapy, maximizing radiation dose to the tumor while minimizing dose to nearby normal tissues.

Also known as: SRBT, stereotactic ablative radiotherapy, SABR

SBRT followed by Durvalumab+Tremelimumab

Eligibility Criteria

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

You may qualify if:

• 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 1.1.
• 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.
• Adequate normal organ and marrow function as defined below:
• Hemoglobin ≥ 9.0 g/dL
• Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L (\> 1500 per mm\^3)
• Platelet count ≥ 100 x 10\^9/L (\>100,000 per mm\^3)
• Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not apply for participants with confirmed Gilbert's syndrome, who will be allowed in consultation with their physician.

You may not qualify if:

• 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:
• Malignancy treated with curative intent and with no known active disease ≥2 years
• Non-metastatic prostate adenocarcinoma, or treated superficial non-invasive bladder cancer
• Adequately treated carcinoma in situ without evidence of disease (eg, cervical cancer in situ)
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) ≤ 14 days of registration

Sponsors & Collaborators

• University of Wisconsin, Madison: lead
• AstraZeneca: collaborator

Study Sites (1)

University of Wisconsin Carbone Cancer Center

Madison, Wisconsin, 53792, United States

Location

Related Links

• UW Carbone Cancer Center home page

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

durvalumab; tremelimumab; Radiosurgery

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Radiotherapy; Therapeutics; Stereotaxic Techniques; Neurosurgical Procedures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Michael Bassetti, MD, PhD

  University of Wisconsin, Madison

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 5, 2017
• First Posted: September 7, 2017
• Study Start: February 20, 2018
• Primary Completion: July 1, 2020
• Study Completion: July 1, 2020
• Last Updated: May 15, 2023

Record last verified: 2023-05

Locations

US (1)