Image Guided Hypofractionated Radiation Therapy, Nelfinavir Mesylate, Pembrolizumab, Nivolumab and Atezolizumab in Treating Patients With Advanced Melanoma, Lung, or Kidney Cancer

• ClinicalTrials.gov Identifier: NCT03050060
• Recruitment Status: Terminated
• First Posted: February 10, 2017
• Results First Posted: June 22, 2022
• Last Update Posted: June 22, 2022
• Sponsor: University of Washington
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Ramesh Rengan, University of Washington

Study Description

Brief Summary:

This phase II trial studies how well image guided hypofractionated radiation therapy works with nelfinavir mesylate, pembrolizumab, nivolumab, and atezolizumab in treating patients with melanoma, lung cancer, or kidney cancer that has spread (advanced). Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. Nelfinavir mesylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, nivolumab and atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving hypofractionated radiation therapy, nelfinavir mesylate, pembrolizumab, nivolumab and atezolizumab may work better in treating patients with melanoma, lung, or kidney cancer.

Condition or disease	Intervention/treatment	Phase
Metastatic Kidney Carcinoma; Recurrent Lung Non-Small Cell Carcinoma; Stage IV Cutaneous Melanoma AJCC v6 and v7; Stage IV Renal Cell Cancer AJCC v7; Stage IV Lung Non-Small Cell Cancer AJCC v7	Drug: Atezolizumab; Radiation: Hypofractionated Radiation Therapy; Other: Laboratory Biomarker Analysis; Drug: Nelfinavir Mesylate; Biological: Nivolumab; Biological: Pembrolizumab	Phase 2

Detailed Description:

OUTLINE:

Beginning 7-14 days prior to start of pembrolizumab, nivolumab, or atezolizumab, patients receive nelfinavir mesylate orally (PO) twice daily (BID) on days 1-7 or 1-14 (dependent upon when treatment is started) up to 11-12 weeks. Patients also receive pembrolizumab, nivolumab or atezolizumab intravenously (IV) over 30-60 minutes on day 1. Cycles repeat every 21-28 days in the absence of disease progression or unacceptable toxicity. Patients then undergo hypofractionated radiation therapy over 3-14 days starting after cycle 1 and before cycle 3 of pembrolizumab, nivolumab or atezolizumab.

After completion of study treatment, patients are followed up at 30 days and then every 6 months for up to 2 years.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 21 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: ImmunoRad: Stratified Phase II Trial of Image Guided Hypofractionated Radiotherapy With Concurrent Nelfinavir and Immunotherapy in Advanced Melanoma, Lung Cancer, and Renal Cell Carcinoma
• Actual Study Start Date: June 9, 2017
• Actual Primary Completion Date: October 1, 2018
• Actual Study Completion Date: July 12, 2020

Arms and Interventions

Arm

Intervention/treatment

Experimental: Treatment (nelfinavir, immunotherapy, radiation therapy); Beginning 7-14 days prior to start of pembrolizumab, nivolumab, or atezolizumab, patients receive nelfinavir mesylate PO BID on days 1-7 or 1-14 (dependent upon when treatment is started) up to 11-12 weeks. Patients also receive pembrolizumab, nivolumab or atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 21-28 days in the absence of disease progression or unacceptable toxicity. Patients then undergo hypofractionated radiation therapy over 3-14 days starting after cycle 1 and before cycle 3 of pembrolizumab, nivolumab or atezolizumab. The study will exclude irradiation of liver metastases as an added precaution.

Drug: Atezolizumab; Given IV; Other Names: MPDL 3280A; MPDL 328OA; MPDL-3280A; MPDL3280A; MPDL328OA; RG7446; RO5541267; Tecentriq; Radiation: Hypofractionated Radiation Therapy; Undergo hypofractionated radiation therapy; Other Names: Hypofractionated Radiotherapy; hypofractionation; Radiation, Hypofractionated; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Nelfinavir Mesylate; Given PO; Other Names: AG1343; Viracept; Biological: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo; Biological: Pembrolizumab; Given IV; Other Names: Keytruda; Lambrolizumab; MK-3475; SCH 900475

Outcome Measures

Primary Outcome Measures :

1. Response Rate [ Time Frame: Up to 6 months after initiating treatment ]
   Will be determined by immune-related Response Evaluation Criteria in Solid Tumor 1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT Scan: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.",

Secondary Outcome Measures :

1. Overall Survival [ Time Frame: From start of study treatment to death due to any cause, assessed up to 2 years ]
   Any long term data in the medical record that showed survival was use to measure overall survival.
2. Progression-free Survival [ Time Frame: From start of treatment to progression by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, symptomatic deterioration, or death due to any cause, assessed up to 2 years ]
   No RECIST measurable progression over the course of 2 years post-treatment. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
3. Number of Adverse Events [ Time Frame: Adverse events were assessed up to 6 months from start of study treatment and All Cause Mortality was assessed upto 2 years from start of study treatment. ]
   Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. All adverse events that were attributable to study intervention in 20 participants, and counted the frequency of severity levels in the participants.
4. Immune Correlative Studies: Changes in T-cell Repertoire [ Time Frame: Up to 6 months ]
   Changes in T-cell receptor diversity

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Disease eligibility and stage

  • Histologically confirmed diagnosis of melanoma, non-small cell lung cancer (NSCLC), or renal carcinoma
  • Previously treated or previously untreated stage IV melanoma, stage IV or recurrent lung cancer, and metastatic renal cancer by American Joint Committee on Cancer (AJCC) staging criteria
  • Presence of a lesion that is suitable for hypofractionated radiotherapy
• Subjects must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria independent of the lesion to be irradiated. Prior checkpoint inhibitor immunotherapy or chemotherapy is allowed as long as the last dose was received > 14 days prior to enrollment
• Eastern Cooperative Oncology Group (ECOG) 0-2
• Acceptable marrow function and hematologic indices for PD1/PDL1 immune checkpoint inhibitor and nelfinavir as per standard of care
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Subjects who have had immunotherapy, chemotherapy, or radiation therapy within 14 days (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
• Subjects may not be receiving other investigational agents
• Patients with untreated/active brain metastases as documented by computed tomography (CT) or magnetic resonance imaging (MRI) within 2 months of study enrollment; by active brain metastases - we mean - actively symptomatic brain metastases requiring steroids
• Allergy or intolerance to nelfinavir or selected PD1/PDL1 immune checkpoint inhibitor
• Patients requiring steroids or other immunosuppressive therapy; low-dose or topical steroids are allowable if being used as replacement therapy
• Patients receiving anti-retroviral therapy or other agents that are contra-indicated with nelfinavir due to drug-drug interactions*
• Pregnant or lactating patients

• Prior radiation that precludes delivery of hypofractionated radiotherapy

  • *For a study regarding the safety and efficacy of high dose nelfinavir on patients with Kaposi's Sarcoma (KS), exclusion criteria included participants who were receiving any "strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 19 (2C19)"

Strong Inhibitors of CYP3A4:

• Antibiotics: clarithromycin, erythromycin, telithromycin, troleandomycin
• HIV: non-nucleoside reverse transcriptase inhibitors (delavirdine, nevirapine), protease inhibitors (ritonavir, indinavir, lopinavir/ritonavir, saquinavir), cobicistat-boosted antiretrovirals (e.g., elvitegravir); NOTE: Clinical trials have demonstrated that there are no clinically significant drug-drug interactions between nelfinavir and the following antiretrovirals: efavirenz (strong CYP3A4 inhibitor), etravirine (strong CYP3A4 inhibitor); therefore, these antiretrovirals will not be excluded. • Antifungals: itraconazole, ketoconazole, voriconazole, fluconazole, posaconazole
• Antidepressants: nefazodone
• Antidiuretic: conivaptan
• GI: cimetidine, aprepitant
• Hepatitis C: boceprevir, telaprevir
• Miscellaneous: seville oranges, grapefruit, or grapefruit juice and/or pomelos, star fruit, exotic citrus fruits, or grapefruit hybrids.

Strong Inducers of CYP3A4:

• Glucocorticoids: cortisone (> 50 mg), hydrocortisone (> 40 mg), prednisone (> 10 mg), methylprednisolone (> 8 mg), dexamethasone (> 1.5 mg)
• Anticonvulsants: phenytoin, carbamazepine, primidone, phenobarbital and other enzyme inducing anti-convulsant drugs (EIACD)
• Antibiotics: rifampin (rifampicin), rifabutin, rifapentine
• Miscellaneous: St. John's Wort, modafinil

Strong Inhibitors of CYP2C9:

• Antifungals: fluconazole; lists including medications and substances known or with the potential to interact with the CYP3A or 2C19

Contacts and Locations

Locations

United States, Washington

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, United States, 98109

Sponsors and Collaborators

University of Washington

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Ramesh Rengan; Fred Hutch/University of Washington Cancer Consortium

  Study Documents (Full-Text)

Documents provided by Ramesh Rengan, University of Washington:

Study Protocol and Statistical Analysis Plan  [PDF] March 4, 2021

Informed Consent Form  [PDF] February 4, 2021

More Information

• Responsible Party: Ramesh Rengan, Professor, University of Washington
• ClinicalTrials.gov Identifier: NCT03050060
• Other Study ID Numbers: 9712; NCI-2016-01816 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 9712 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium ); P30CA015704 ( U.S. NIH Grant/Contract ); RG3117000 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
• First Posted: February 10, 2017
• Results First Posted: June 22, 2022
• Last Update Posted: June 22, 2022
• Last Verified: May 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Ramesh Rengan, University of Washington:

Kidney; Lung; Melanoma, Skin

Additional relevant MeSH terms:

Carcinoma; Melanoma; Carcinoma, Renal Cell; Carcinoma, Non-Small-Cell Lung; Kidney Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nevi and Melanomas; Adenocarcinoma; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Nelfinavir; Pembrolizumab; Nivolumab; Atezolizumab