Genomically Guided Radiation Therapy for the Management of Stage II-III Locally Advanced and Unresectable Non-Small Cell Lung Cancer

Status: closed to accrual and intervention

This early phase I trial tests the feasibility of genomically guided radiation therapy (RT) with standard chemotherapy in treating patients with stage II-III non-small cell lung cancer (NSCLC) that has spread to nearby tissue or lymph nodes (locally advanced) and that cannot be removed by surgery (unresectable). Genomically adjusted radiation dose (GARD) RT uses genetic information specific to the patient's cancer in order to customize the amount of radiation given along with concurrent chemotherapy based on the patient's radiosensitivity index (RSI). RSI is an assay performed on the biopsied tissue that will help determine how the tumor may respond to radiation therapy. GARD radiation therapy uses high-energy X-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. This customized radiation treatment may be a safe and effective way of controlling patients with NSCLC.

Inclusion Criteria

Diagnosis of American Joint Committee on Cancer (AJCC) stage 2 or stage 3 unresectable NSCLC as determined by a multidisciplinary oncology team
Confirmation of NSCLC with availability of fresh tumor biopsy by tissue biopsy which can include adenocarcinoma, squamous cell, large cell carcinoma, or NSCLC not otherwise specified
Life expectancy > 12 weeks
Creatinine < 1.5 x upper limit of normal (ULN)
Bilirubin < 1.5 x ULN
Transaminases < 3.0 x ULN, except in known hepatic disease, wherein may be < 5 x ULN
White blood cells >= 2.5
Neutrophils >= 1000
Platelets >= 50,000
Hemoglobin >= 8
Eastern Cooperative Oncology Group (ECOG) 0-1
Age >= 18 years
Patients with surgery within 14 days should have recovered from all effects of the surgery and be cleared by their surgeon
There is no limit on prior systemic or therapies
Women of childbearing potential and sexually active males must commit to the use of effective contraception while on study
Ability to sign an informed consent form, which can be signed by a family member or health care proxy. Informed consent must be given before any study related procedures occur

Exclusion Criteria

Current or prior participation in a study of an investigational agent or investigational device within 2 weeks of the first dose of study treatment
Major surgery or significant traumatic injury that has not been recovered from 14 days before the initiation of study drug
Women who are pregnant or breastfeeding
History of allergy or hypersensitivity to any of the study drugs or study drug components
Concurrent brain metastases or leptomeningeal disease
History of prior malignancy within 2 years prior to screening, with the exception of those with a negligible risk of metastasis or death (e.g., 5-year OS of > 90%), such as but not limited to, non-melanoma skin carcinoma, ductal carcinoma in situ, or stage I endometriod uterine cancer, and others at the discretion of the principal investigator (PI)
Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, 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 (eg, 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 principal investigator * Patients with celiac disease controlled by diet alone
Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion: * Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular injection) * Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent * Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication)

PRIMARY OBJECTIVES:

I. To evaluate the number of participants able to undergo biopsy with successful estimation of prescription radiosensitivity index (RxRSI) for use personalizing radiotherapy among patients with unresectable locally advanced NSCLC.

II. To evaluate safety utilizing genomically guided dose escalation among patients with locally advanced unresectable NSCLC.

SECONDARY OBJECTIVES:

I. To determine the two year freedom from local regional progression following genomically guided dose escalation among patients with unresectable locally advanced NSCLC.

II. To determine the median and 2 year progression-free survival (PFS) following genomically guided dose escalation among patients with locally advanced unresectable NSCLC.

III. To determine the median and 2 year overall survival (OS) following genomically guided dose escalation among patients with locally advanced unresectable NSCLC.

OUTLINE: Patients are assigned to 1 of 3 arms based on RxRSI estimates.

ARM A: Patients undergo biopsy for RSI testing at baseline and receive standard of care (SOC) platinum doublet chemotherapy intravenously (IV) on week -3 and on weeks 1-6 in the absence of disease progression or unacceptable toxicity. Patients with RxRSI score =< 60Gy receive a standard dose of GARD-RT for 30 fractions 5 days a week on weeks 1-8 in the absence of disease progression or unacceptable toxicity. Patients then receive SOC durvalumab within 42 days following completion of radiation therapy and for each cycle. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity.

ARM B: Patients undergo biopsy for RSI testing at baseline and receive SOC platinum doublet chemotherapy IV on week -3 and on weeks 1-6 in the absence of disease progression or unacceptable toxicity. Patients with RxRSI score > 60Gy receive an escalated dose of GARD-RT for 5 days a week on weeks 1-8 in the absence of disease progression or unacceptable toxicity. Patients then receive SOC durvalumab within 42 days following completion of radiation therapy and for each cycle. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity.

ARM C: Patients undergo biopsy for RSI testing at baseline and receive SOC platinum doublet chemotherapy IV on week -3 and on weeks 1-6 in the absence of disease progression or unacceptable toxicity. Patients without RxRSI scores receive a standard dose of GARD-RT for 30 fractions 5 days a week on weeks 1-8 in the absence of disease progression or unacceptable toxicity. Patients then receive SOC durvalumab within 42 days following completion of radiation therapy and for each cycle. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity.

Patients in all arms also undergo positron emission tomography (PET)/computed tomography (CT), CT, and/or magnetic resonance imaging (MRI) at baseline and every 3 months during follow-up, as well as collection of blood at screening, week 10, every 3 months during follow-up, and at disease progression. Patients may optionally undergo a biopsy at time of progression.

After completion of the study treatment, patients are followed up every 3 months for up to 2 years.

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Genomically Guided Radiation Therapy for the Management of Stage II-III Locally Advanced and Unresectable Non-Small Cell Lung Cancer

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