Targeting PD-1 Therapy Resistance With Focused High or High and Low Dose Radiation in SCCHN

• ClinicalTrials.gov Identifier: NCT03085719
• Recruitment Status: Recruiting
• First Posted: March 21, 2017
• Last Update Posted: November 29, 2022
• Sponsor: Dana-Farber Cancer Institute
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Jonathan Schoenfeld, MD, MPH, Dana-Farber Cancer Institute

Study Description

Brief Summary:

This research study is studying immunotherapy in combination with radiation therapy as a possible treatment for head & neck cancer that has worsened or spread to another organ or part of your body.

The immunotherapy involved in this study is: MK-3475 (pembrolizumab or KEYTRUDA).

Condition or disease	Intervention/treatment	Phase
Head and Neck Cancer	Drug: Pembrolizumab; Radiation: Radiation	Phase 2

Detailed Description:

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational treatment to learn whether the treatment works in treating a specific disease. "Investigational" means that the treatment is being studied.

MK-3475 is a humanized monoclonal antibody. An antibody is a common type of protein made in the body in response to a foreign substance (particles not typically found in the body such as bacteria or viruses). Antibodies attack foreign substances and protect against infection. Antibodies can also be produced in the laboratory for use in treating patients. MK-3475 is designed to restore the natural ability of the immune system to recognize and target cancer cells.

The FDA recently granted approval to MK-3475 as a treatment for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). This study is testing whether using radiation in combination with MK-3475 will make this drug work better in participants that might otherwise be unlikely to benefit from this drug because they have not responded to either this same drug given without radiation or another similar drug.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 26 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Targeting PD-1 Therapy Resistance With Focused High or High and Low Dose Radiation in Squamous Cell Carcinoma of the Head and Neck (SCCHN)
• Actual Study Start Date: June 30, 2017
• Estimated Primary Completion Date: October 31, 2023
• Estimated Study Completion Date: October 31, 2027

Arms and Interventions

Arm	Intervention/treatment
Experimental: High Dose Radiation + Pembrolizumab; High dose radiation will be given in 3 fractions; Pembrolizumab administered intravenously on day one of each cycle.	Drug: Pembrolizumab; Keytruda is designed to restore the natural ability of the immune system to recognize and target cancer cells; Other Name: Keytruda; Radiation: Radiation; Radiation is used to shrink the cancer
Experimental: High Dose + Low Dose Radiation + Pembrolizumab; High Dose radiation will be given in 3 fractions; Low Dose Radiation will be given in 2 fractions; Pembrolizumab administered intravenously on day one of each cycle.	Drug: Pembrolizumab; Keytruda is designed to restore the natural ability of the immune system to recognize and target cancer cells; Other Name: Keytruda; Radiation: Radiation; Radiation is used to shrink the cancer

Outcome Measures

Primary Outcome Measures :

1. Overall Response Rate [ Time Frame: 1 year ]

Secondary Outcome Measures :

1. Overall Survival [ Time Frame: 1 year ]
2. Progression Free Survival [ Time Frame: 1 year ]
3. Number of patients with treatment related adverse events as assessed by CTCAE v4.0 [ Time Frame: 1 year ]
4. Objective response by immune related response criteria (irRC) [ Time Frame: 1 year ]
5. Local Response determined using CT imaging [ Time Frame: 1 year ]
6. Clinical Benefit Rate [ Time Frame: 1 year ]
7. Abscopal response determined using CT imaging [ Time Frame: 1 year ]

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:

• Pathologically confirmed squamous cell carcinoma of the head and neck with evidence of metastatic disease considered incurable by local therapies. Patients without pathologic or cytologic evidence of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluation.
• Patients must have evidence of radiologic or clinical disease progression during previous treatment with systemic PD-1 directed therapy, or have stable disease on prior PD-1 therapy (at least 6 doses) and/or have been deemed not to derive clinical benefit from PD-1 directed treatment.
• Patients must have least 3 measurable non-CNS based lesions that have not previously been irradiated. Palliative radiation must be potentially indicated for at least one of these lesions.
• Patients must agree to undergo a research biopsy, if tumor is accessible, at baseline (mandatory) and at the end of cycle 2 of pembrolizumab (optional). .
• Prior systemic therapy: Patients must be at least 2 weeks from prior chemotherapy, biological agents, immunotherapy or any investigational drug product, with adequate recovery of toxicity. For investigational agents, the minimum time from prior therapy is 5 half-lives if this is longer than 2 weeks in duration.
• Prior radiation therapy: Patients must be at least 2 weeks from prior radiation therapy
• Concurrent administration of other cancer specific therapy during the course of this study is not allowed.
• Only patients 18 years and older are eligible. There is no upper age limit but the patients must be able to medically tolerate the regimen. Adverse event data are currently unavailable on the use immune checkpoint blockade for participants < 18 years of age, and thus children are excluded from this study.
• ECOG performance status <=1 (see Appendix A).
• Ability to understand and the willingness to sign a written informed consent document
• Female subjects of childbearing potential must have a negative serum pregnancy test at screening.

• Female and male subjects of childbearing potential must agree to use an adequate method of contraception as outlined in section 5.7.1. Contraception is required prior to study entry and for the duration of study participation and 4 months after completion of pembrolizumab administration.

  --Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

• Participants must have normal organ and marrow function as defined below:

  • leukocytes ≥3,000/mcl
  • absolute neutrophil count ≥1,500/mcL
  • platelets ≥100,000/mcL
  • hemoglobin >= 9 g/dl
  • total bilirubin ≤1.5 × institutional upper limit of normal (ULN)
  • AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN
  • AST(SGOT)/ALT(SGPT) For patients with documented liver metastases, ≤ 5 × institutional ULN
  • creatinine ≤1.5 ×within normal institutional ULN OR
  • creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels above institutional ULN.
  • International normalized ratio (INR) or Prothrombin Time (PT) <1.5 times the upper limit of normal unless subject is receiving anticoagulant therapy, as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
  • Activated Partial Thromboplastin Time (aPTT) <1.5 times the upper limit of normal unless subject is receiving anticoagulant therapy, as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
• Laboratory tests required for eligibility must be completed within 14 days prior study entry. Baseline tumor measurements must be documented from tests within 28 days of study entry. Other non-laboratory tests must be performed within 28 days of study entry.

Exclusion Criteria:

• Metastatic disease impinging on the spinal cord or threatening spinal cord compression.
• Surgical fixation of bone lesion to be irradiated is required and indicated to provide mechanical stability.
• Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms. Participants with previously diagnosed brain metastases are eligible if they have completed treatment at least 2 weeks prior to trial therapy initiation, are neurologically stable, and have recovered from the acute effects of radiotherapy or surgery. Any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for ≥2 weeks before the initiating protocol therapy. Treatment for brain metastases may include surgery, whole brain radiotherapy, radiosurgery, or a combination as deemed appropriate by the treating physician.
• Participants who are receiving any other investigational agents.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to pembrolizumab or previous toxicity attributed to pembrolizumab or other PD-1 directed therapy that led to drug discontinuation.
• Uncontrolled intercurrent illness including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Clinically significant electrocardiogram (ECG) abnormality, including a marked Baseline prolonged QT/QTc ([QT interval/corrected QT interval], e.g., a repeated demonstration of a QTc interval >500 ms).
• Pregnant women are excluded from this study because immunotherapy has the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with immunotherapy, breastfeeding should be discontinued if the mother is treated on this protocol.
• Individuals with a history of a different malignancy are ineligible except for the following circumstances: if they have been disease-free for at least 2 years and are deemed by the investigator to be at low risk for recurrence of that malignancy; or if diagnosed and treated for cervical cancer in situ or basal cell or squamous cell carcinoma of the skin.
• HIV-positive individuals on combination antiretroviral therapy are ineligible because of the potential for interaction between immunotherapy and these medications.
• Has history of (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non infectious pneumonitis.
• Active, suspected or prior documented autoimmune disease that has required systemic treatment in the last 2 years with immune modifying agents (e.g. replacement therapy such as thyroxine, insulin or physiologic corticosteroids is not an exclusion criteria).
• The subject is known to be positive for HepBsAg, or HCV RNA.
• Lack of availability for follow up assessments.
• The investigator's belief that the subject is medically unfit to receive pembrolizumab and or unsuitable for any other reason.
• Has received a live vaccine within 30 days of planned start of study therapy

Contacts and Locations

Contacts

Contact: Jonathan D. Schoenfeld, MD MPH; 617-632-5734; jdschoenfeld@partners.org

Contact: shana Criscitiello; 6175828942; scriscitiello@bwh.harvard.edu

Locations

United States, Massachusetts

Dana Farber Cancer Institute; Recruiting

Boston, Massachusetts, United States, 02215

Contact: Jonathan D. Schoenfeld, MD MPH 617-632-5734

Principal Investigator: Jonathan D. schoenfeld, MD

Sponsors and Collaborators

Dana-Farber Cancer Institute

Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Jonathan D. Schoenfeld, MD MPH; Dana-Farber Cancer Institute

More Information

• Responsible Party: Jonathan Schoenfeld, MD, MPH, MD, MPH, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT03085719
• Other Study ID Numbers: 16-604
• First Posted: March 21, 2017
• Last Update Posted: November 29, 2022
• Last Verified: November 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 Jonathan Schoenfeld, MD, MPH, Dana-Farber Cancer Institute:

Head and Neck Cancer

Additional relevant MeSH terms:

Head and Neck Neoplasms; Neoplasms by Site; Neoplasms; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents