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

Primary Purpose

Metastatic Kidney Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Stage IV Cutaneous Melanoma AJCC v6 and v7

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Atezolizumab
Hypofractionated Radiation Therapy
Laboratory Biomarker Analysis
Nelfinavir Mesylate
Nivolumab
Pembrolizumab
Sponsored by
University of Washington
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Metastatic Kidney Carcinoma focused on measuring Kidney, Lung, Melanoma, Skin

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Fred Hutch/University of Washington Cancer Consortium

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (nelfinavir, immunotherapy, radiation therapy)

Arm Description

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.

Outcomes

Primary Outcome Measures

Response Rate
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

Overall Survival
Any long term data in the medical record that showed survival was use to measure overall survival.
Progression-free Survival
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
Number of Adverse Events
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.
Immune Correlative Studies: Changes in T-cell Repertoire
Changes in T-cell receptor diversity

Full Information

First Posted
February 8, 2017
Last Updated
May 26, 2022
Sponsor
University of Washington
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT03050060
Brief Title
Image Guided Hypofractionated Radiation Therapy, Nelfinavir Mesylate, Pembrolizumab, Nivolumab and Atezolizumab in Treating Patients With Advanced Melanoma, Lung, or Kidney Cancer
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
Study Type
Interventional

2. Study Status

Record Verification Date
May 2022
Overall Recruitment Status
Terminated
Why Stopped
Terminated due to slow accrual
Study Start Date
June 9, 2017 (Actual)
Primary Completion Date
October 1, 2018 (Actual)
Study Completion Date
July 12, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Washington
Collaborators
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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
Keywords
Kidney, Lung, Melanoma, Skin

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
21 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (nelfinavir, immunotherapy, radiation therapy)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Atezolizumab
Other Intervention Name(s)
MPDL 3280A, MPDL 328OA, MPDL-3280A, MPDL3280A, MPDL328OA, RG7446, RO5541267, Tecentriq
Intervention Description
Given IV
Intervention Type
Radiation
Intervention Name(s)
Hypofractionated Radiation Therapy
Other Intervention Name(s)
Hypofractionated Radiotherapy, hypofractionation, Radiation, Hypofractionated
Intervention Description
Undergo hypofractionated radiation therapy
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Drug
Intervention Name(s)
Nelfinavir Mesylate
Other Intervention Name(s)
AG1343, Viracept
Intervention Description
Given PO
Intervention Type
Biological
Intervention Name(s)
Nivolumab
Other Intervention Name(s)
BMS-936558, MDX-1106, NIVO, ONO-4538, Opdivo
Intervention Description
Given IV
Intervention Type
Biological
Intervention Name(s)
Pembrolizumab
Other Intervention Name(s)
Keytruda, Lambrolizumab, MK-3475, SCH 900475
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Response Rate
Description
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.",
Time Frame
Up to 6 months after initiating treatment
Secondary Outcome Measure Information:
Title
Overall Survival
Description
Any long term data in the medical record that showed survival was use to measure overall survival.
Time Frame
From start of study treatment to death due to any cause, assessed up to 2 years
Title
Progression-free Survival
Description
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
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
Title
Number of Adverse Events
Description
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.
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.
Title
Immune Correlative Studies: Changes in T-cell Repertoire
Description
Changes in T-cell receptor diversity
Time Frame
Up to 6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ramesh Rengan
Organizational Affiliation
Fred Hutch/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fred Hutch/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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