Radiation Therapy and MK-3475 for Patients With Recurrent/Metastatic Head and Neck Cancer, Renal Cell Cancer, Melanoma, and Lung Cancer

February 26, 2024 updated by: Sidney Kimmel Cancer Center at Thomas Jefferson University

An Exploratory Study to Investigate the Immunomodulatory Activity of Radiation Therapy (RT) in Combination With MK-3475 in Patients With Recurrent/Metastatic Head and Neck, Renal Cell Cancer, Melanoma and Lung Cancer

This randomized clinical trial studies radiation therapy and MK-3475 in treating patients with head and neck cancer, kidney cancer, melanoma, or lung cancer that has returned, has spread to other parts of the body, or cannot be removed by surgery. Radiation therapy uses high-energy x-rays to kill tumor cells. Monoclonal antibodies, such as MK-3475, may block tumor growth by targeting certain cells and causing the immune system to attack the tumor. Studying the effects of MK-3475 with radiation therapy on the body may help doctors learn whether it may be an effective treatment for these solid tumors.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

PRIMARY OBJECTIVES:

I. To investigate the immunomodulatory activity of radiation therapy (RT) or RT in combination with anti-programmed cell death 1 (PD)-1 antibody (MK-3475) in patients with recurrent/metastatic head and neck cancer, renal cell cancer, melanoma and lung cancer.

SECONDARY OBJECTIVES:

I. To explore whether programmed cell death ligand 1 (PD-L1) expression is associated with treatment response to the combination of RT and PD-1 blockade in renal cell cancer (RCC), head and neck cancer (HNC), lung cancer and melanoma.

II. To explore whether circulating tumor cells can be used to determine PD-L1 expression.

III. To explore other immune-related biomarker changes after RT: soluble PD-L1, cytokines etc.

OUTLINE: Patients are randomized to 1 of 4 treatment arms.

ARM A1: Patients undergo radiation therapy on day 1 per standard of care and then undergo biopsy 3-10 days later. Beginning 0-7 days after biopsy, patients receive MK-3475 intravenously (IV) over 30 minutes on day 1. Courses of MK-3475 repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM A2: Patients undergo radiation therapy on days 1-5 and then undergo biopsy 3-10 days later. Beginning 0-7 days after biopsy, patients receive MK-3475 as in Arm A1.

ARM B1: Patients receive one dose of MK-3475 IV over 30 minutes on day 1 and then undergo 1 fraction of RT. Patients then receive MK-3475 IV over 30 minutes in the absence of disease progression or unacceptable toxicity.

ARM B2: Patients receive MK-3475 as in Arm B1 and undergo 5 fractions of RT.

After completion of study treatment, patients are followed up at approximately 30 days and then every 8 weeks.

Study Type

Interventional

Enrollment (Actual)

41

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19107
        • Sidney Kimmel Cancer Center at Thomas Jefferson University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Be willing and able to provide written informed consent/assent for the trial.
  2. Be ≥ 18 years of age on day of signing informed consent.
  3. Have provided tissue from an archival tissue sample ( < 6 months old) or newly obtained core biopsy of a tumor lesion before radiation therapy. A core biopsy will be required. It is mandatory to have post-radiation re-biopsy.
  4. In addition to index lesion, there are ≥ 1 measurable lesion(s).
  5. Have a performance status of ≤ 1 on the ECOG Performance Scale.

  6. Demonstrate adequate organ function defined as the following:

    • Absolute neutrophil count (ANC) ≥1,500 /mcL
    • Platelets ≥100,000 / mcL
    • Hemoglobin ≥9 g/dL or ≥5.6 mmol/L

    • Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.8 X upper limit of normal (ULN) OR

      ≥50 mL/min for subject with creatinine levels > 1.8 X institutional ULN

    • Serum total bilirubin ≤ 1.5 X ULN OR direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
    • AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
  7. Female subjects of childbearing potential should have a negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  8. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication (Reference Section 5.7.2). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
  9. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.

Exclusion Criteria:

  1. Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 2 weeks of the radiation therapy.
  2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the radiation therapy.
  3. Has had a prior monoclonal antibody within 4 weeks prior to radiation therapy or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.

  4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to radiation therapy or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.

    • Note: Prior radiation therapy does not necessary excludes patients. The index lesion may be acceptable for stereotactic radiosurgery (SRS) and this will be determined by radiation oncologist.
    • Note: If there are more than one symptomatic lesions, patients will be excluded if the lesions can't be encompassed within one radiation portal.
    • Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
    • Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
  5. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer or in situ cervical cancer that has undergone potentially curative therapy.
  6. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the radiation therapy and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to radiation treatment.
  7. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study.
  8. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
  9. Has an active infection requiring systemic therapy.
  10. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  11. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  12. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
  13. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
  14. Has a known Human Immunodeficiency Virus infection (HIV 1/2 antibodies) or Acquired Immunodeficiency Syndrome((HIV/AIDS).
  15. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
  16. Has received a live vaccine within 30 days prior to the radiation therapy.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: A1: RT (1 fraction, 8 Gy) + MK-3475
Patients undergo RT on day 1 per standard of care and then undergo biopsy 3-10 days later. Beginning 0-7 days after biopsy, patients receive MK-3475 IV over 30 minutes on day 1. Courses of MK-3475 repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Radiation: Radiation Therapy (RT)
Undergo RT
Other Names:
  • Radiation
  • Radiotherapy
Drug: MK-3475
Given IV
Other Names:
  • Keytruda
  • Pembrolizumab
  • lambrolizumab
Experimental: A2: RT (5 fractions, 4 Gy) + MK-3475
Patients undergo RT on days 1-5 and then undergo biopsy 3-10 days later. Beginning 0-7 days after biopsy, patients receive MK-3475 as in Arm A1.
Radiation: Radiation Therapy (RT)
Undergo RT
Other Names:
  • Radiation
  • Radiotherapy
Drug: MK-3475
Given IV
Other Names:
  • Keytruda
  • Pembrolizumab
  • lambrolizumab
Experimental: B1: MK-3475 + RT (1 fraction, 8 Gy) + MK-3475
Patients receive one dose of MK-3475 IV over 30 minutes on day 1 and then undergo 1 fraction of RT. Patients then receive MK-3475 IV over 30 minutes in the absence of disease progression or unacceptable toxicity.
Radiation: Radiation Therapy (RT)
Undergo RT
Other Names:
  • Radiation
  • Radiotherapy
Drug: MK-3475
Given IV
Other Names:
  • Keytruda
  • Pembrolizumab
  • lambrolizumab
Experimental: B2: MK-3475 + RT (5 fractions, 4 Gy) + MK-3475
Patients receive MK-3475 as in Arm B1 and undergo 5 fractions of RT.
Radiation: Radiation Therapy (RT)
Undergo RT
Other Names:
  • Radiation
  • Radiotherapy
Drug: MK-3475
Given IV
Other Names:
  • Keytruda
  • Pembrolizumab
  • lambrolizumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in PD-LI levels
Time Frame: Baseline to up to 10 days after last dose of RT
Within each cohort, the significance of change in PD-L1 will be assessed using an exact one-sided sign test. The null hypothesis is that the average change (post-pre) is less than or equal to 0 while the alternative hypothesis is that the average change is greater than 0. The proportion of patients with improvement will be estimated along with an exact 95% confidence interval. As an exploratory analysis, the proportion will also be estimated separately within each cohort for the head and neck cancer patients.
Baseline to up to 10 days after last dose of RT

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Response rate
Time Frame: Up to 4 years
Summarized by treatment cohort along with exact 95% binomial confidence intervals.
Up to 4 years
Rate of toxicities
Time Frame: Up to 4 years
Summarized by treatment cohort along with exact 95% binomial confidence intervals.
Up to 4 years
Progression-free survival
Time Frame: Up to 4 years
Estimated by treatment cohort using the Kaplan-Meier method.
Up to 4 years
Biomarker levels
Time Frame: Up to 10 days after last dose of RT
Repeated biomarker measurements will be modeled using mixed effects linear regression.
Up to 10 days after last dose of RT

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sidney Kimmel Cancer Center at Thomas Jefferson University

Collaborators

Merck Sharp & Dohme LLC

Investigators

  • Principal Investigator: Jennifer Johnson, MD, PhD, Sidney Kimmel Cancer Center at Thomas Jefferson University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 5, 2015

Primary Completion (Actual)

June 5, 2018

Study Completion (Actual)

March 25, 2021

Study Registration Dates

First Submitted

December 11, 2014

First Submitted That Met QC Criteria

December 11, 2014

First Posted (Estimated)

December 17, 2014

Study Record Updates

Last Update Posted (Actual)

February 28, 2024

Last Update Submitted That Met QC Criteria

February 26, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 14P.524
  • 2014-085 (Other Identifier: CCRRC)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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