HDCRT Plus Pembrolizumab in Advanced Malignancies (UVA-AM-001)

A Pilot Study to Assess the Combination of High-Dose Conformal Radiation Therapy (HDCRT) and Pembrolizumab in Modulating Local and Systemic T-cell Responses in Advanced Malignancies

This study is a pilot study to evaluate high-dose conformal radiation therapy (HDCRT) administered in combination with pembrolizumab in patients with solid tumors.

Study Overview

• Status: Completed
• Conditions: Solid Tumor
• Intervention / Treatment: Drug: Pembrolizumab; Radiation: High-Dose Conformal Radiation Therapy

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Subjects must have a histologically or cytologically proven advanced solid tumor malignancy for which palliative radiation is recommended. In solid tumors where pembrolizumab has been approved for use, patients may receive pembrolizumab as indicated, in the context of this protocol. In solid tumors where pembrolizumab has not been approved for use, the following criteria apply:

  • Patients must be resistant to at least 1 prior conventional chemotherapy regimen or other standard of care regimen,
  • Patient must have no remaining conventional treatment options proven to provide long-term disease control, and
  • Patient has declined other conventional treatment options
• Palliative radiation therapy may be recommended for primary tumor and/or any metastatic site that is accessible to biopsy.
• At least one site of disease that is accessible to radiation and multiple biopsies. Subjects may have disease that is encompassed within the radiation field or may have known disease both inside and outside of the radiation field.
• Must be able to provide tissue from 2-3 separate biopsy procedures that will be completed throughout the course of the study.
• A performance status of 0, 1 or 2 on the ECOG Performance Scale.
• Subjects must demonstrate adequate organ function.
• A life expectancy ≥ 6 months.

Exclusion Criteria:

• Requires urgent treatment with cytotoxic chemotherapy or other therapy is indicated.
• A diagnosis of immunodeficiency.
• A known history of active TB (Bacillus Tuberculosis).
• Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with untreated brain metastases and patients who have had brain metastases re-treated with radiation will be excluded. Patients whom have either midline shift, or any signs of herniation (even if disease has been treated with GK) will be excluded. Subjects with previously treated brain metastases may participate provided they are 1) stable (without clinical evidence of progression) 2) are out at least 10 days from CNS radiation and 3) and are not using steroids as part of treatment for their brain lesions for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
• Active autoimmune disease that has required systemic treatment in the past 2 years.
• A history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
• An infection requiring systemic therapy.
• Pregnancy.
• HIV positivity.
• Evidence of active Hepatitis B virus or Hepatitis C virus.
• Significant cardiovascular disease including unstable angina pectoris, uncontrolled hypertension, uncontrolled arrhythmias, or severe valvular heart disease, or a myocardial infarction within 6 months prior to the first dose of study treatment.
• Active bleeding disorders or evidence of chronic or acute disseminated intravascular coagulation (DIC).
• Class III or IV heart disease (New York Heart Association classification).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: HDCRT administered with first dose of pembrolizumab; Pembrolizumab (200 mg) plus HDCRT (24 Gy in 3 fractions of 8 Gy each for bone and/or soft tissue lesions; 30 Gy in 5 fractions of 6 Gy each for the prostate gland) are both administered beginning on day 1. Pembrolizumab (200 mg) will be administered on days 1, 43, 64, 85. Subjects who have measurable disease outside of the radiation field and who have derived benefit from the 4 doses of pembrolizumab may continue to receive pembrolizumab every 3 weeks for up to 2 years. HDCRT will be administered to the primary tumor and/or sites of metastatic disease (1 or more sites permitted) over a period of 3-5 days. The length of time for administration of the HDCRT will depend on the site of disease that is to be radiated. HDCRT will begin on day 1.	Drug: Pembrolizumab; 200 mg; Other Names: Keytruda; MK-3475; Radiation: High-Dose Conformal Radiation Therapy; 24 Gy in 3 fractions of 8Gy each for bone and/or soft tissue lesions 30 Gy in 5 fractions of 6 Gy each for prostate gland; Other Names: HDCRT
Experimental: Arm B: HDCRT administered between doses 1& 2 of pembrolizumab; Pembrolizumab (200 mg) begins on day 1. HDCRT (24 Gy in 3 fractions of 8 Gy each for bone and/or soft tissue lesions; 30 Gy in 5 fractions of 6 Gy each for the prostate gland) begins on day 22. Pembrolizumab (200 mg) will be administered on days 1, 43, 64, 85. Subjects who have measurable disease outside of the radiation field and who have derived benefit from the 4 doses of pembrolizumab may continue to receive pembrolizumab every 3 weeks for up to 2 years. HDCRT will be administered to the primary tumor and/or sites of metastatic disease (1 or more sites permitted) over a period of 3-5 days. The length of time for administration of the HDCRT will depend on the site of disease that is to be radiated. HDCRT will begin on day 22.	Drug: Pembrolizumab; 200 mg; Other Names: Keytruda; MK-3475; Radiation: High-Dose Conformal Radiation Therapy; 24 Gy in 3 fractions of 8Gy each for bone and/or soft tissue lesions 30 Gy in 5 fractions of 6 Gy each for prostate gland; Other Names: HDCRT
Experimental: Arm C: HDCRT administered prior to first dose of pembrolizumab; Pembrolizumab (200 mg) begins on day 1. HDCRT (24 Gy in 3 fractions of 8 Gy each for bone and/or soft tissue lesions; 30 Gy in 5 fractions of 6 Gy each for the prostate gland) begins on day 1. Pembrolizumab will be administered on days 22, 43, 64, and 85. Subjects who have measurable disease outside of the radiation field and who have derived benefit from the four doses of pembrolizumab may continue to receive pembrolizumab every 3 weeks for up to 2 years. HDCRT will be administered to the primary tumor and/or sites of metastatic disease (1 or more sites permitted) over a period of 3-5 days. The length of time for administration of the HDCRT will depend on the site of disease that is to be radiated. HDCRT will begin on day 1.	Drug: Pembrolizumab; 200 mg; Other Names: Keytruda; MK-3475; Radiation: High-Dose Conformal Radiation Therapy; 24 Gy in 3 fractions of 8Gy each for bone and/or soft tissue lesions 30 Gy in 5 fractions of 6 Gy each for prostate gland; Other Names: HDCRT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety: adverse event profile	Obtain preliminary data on the safety of HDCRT with immunotherapy, delivered concurrently (Arm A) or sequentially (Arms B and C)	30 days post-treatment for adverse events; 90 days post-treatment for serious adverse events
Immunologic: effect on T cell tumor infiltration	Estimate the effect of HDCRT, pembrolizumab, and the combination of HDCRT and pembrolizumab on CD8+ T cell and CD4+ T regulatory cell infiltration in tumors.	through day 43

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunologic: effect on lymphocyte composition of blood	Estimate the effect of HDCRT, pembrolizumab, and the combination of HDCRT and pembrolizumab on the lymphocyte composition of blood over time.	up to year 2

Collaborators and Investigators

• Sponsor: James Larner, MD
• Investigators: Principal Investigator: James Larner, MD, University of Virginia

Study record dates

Study Major Dates

• Study Start (Actual): March 21, 2017
• Primary Completion (Actual): January 13, 2020
• Study Completion (Actual): February 10, 2020

Study Registration Dates

• First Submitted: November 30, 2016
• First Submitted That Met QC Criteria: December 5, 2016
• First Posted (Estimate): December 8, 2016

Study Record Updates

• Last Update Posted (Actual): December 16, 2020
• Last Update Submitted That Met QC Criteria: December 11, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: immunotherapy; pembrolizumab; advanced solid tumor; MK-3475; High-dose conformal radiation therapy; HDCRT
• Additional Relevant MeSH Terms: Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Pembrolizumab
• Other Study ID Numbers: 18488

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No