Phase II PEMBROLIZUMAB + PALLIATIVE RADIOTHERAPY IN BC

• ClinicalTrials.gov Identifier: NCT03051672
• Recruitment Status: Terminated
• First Posted: February 14, 2017
• Results First Posted: April 27, 2021
• Last Update Posted: April 27, 2021
• Sponsor: Dana-Farber Cancer Institute
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Sara Tolaney, Dana-Farber Cancer Institute

Study Description

Brief Summary:

This research study is studying radiation therapy in combination with an immunotherapy as a possible treatment for metastatic hormone receptor (HR) positive, HER2-negative breast cancer.

The interventions involved in this study are:

• Palliative Radiotherapy
• Pembrolizumab

Condition or disease	Intervention/treatment	Phase
Metastatic Breast Cancer	Drug: Pembrolizumab; Radiation: Palliative radiotherapy	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 intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied.

In this research study, the investigators are evaluating the safety and effectiveness of palliative radiotherapy ("radiation therapy") in combination with pembrolizumab in HR-positive, HER2-negative breast cancer. This study is designed to test how well radiation therapy in combination with pembrolizumab treats this type of cancer.

The FDA has approved radiation therapy as a treatment option for this type of breast cancer.

The FDA (the U.S. Food and Drug Administration) has not approved pembrolizumab for this specific disease but it has been approved in the United Sates for other types of cancer.

Pembrolizumab is a drug that may treat cancer by working with the immune system. The immune system is the body's natural defense against disease. The immune system sends types of cells called "T cells" throughout the body to detect and fight infections and diseases, including cancer. For some types of cancer, the T cells do not work as they should and are prevented from attacking the tumors. Pembrolizumab is thought to work by blocking a protein in the T cells called PD-1 ("programmed death 1"), which then allows these cells and other parts of the immune system to attack tumors.

The combination of pembrolizumab and radiation therapy is investigational. The study drug and radiation therapy, when given separately, work in different waysto help stop the cancer cells from growing and spreading. However, it is not known if giving the study drug and radiation therapy at the same time will have a better anti-cancer effect than giving each treatment on its own.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 8 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study Of Pembrolizumab In Combination With Palliative Radiotherapy For Metastatic Hormone Receptor Positive Breast Cancer
• Actual Study Start Date: May 22, 2017
• Actual Primary Completion Date: September 4, 2018
• Actual Study Completion Date: January 11, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Pembrolizumab With Radiation; pembrolizumab : 200 mg intravenously 2 to 7 days prior to radiotherapy (RT) and on day 1 of repeating 21-day cycles. Treatment up to 35 cycles. Palliative radiation: a total dose of 20 Gy in 5 fractions	Drug: Pembrolizumab; Pembrolizumab (formerly MK-3475) is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD1 and its ligands, PD-L1 and PD-L2.; Other Name: Keytruda; Radiation: Palliative radiotherapy; Palliative radiotherapy aims to shrink cancer, slow down its growth or control symptoms.

Outcome Measures

Primary Outcome Measures :

1. Objective Response Rate [ Time Frame: Tumor measurements are repeated every 6 weeks for the first 24 weeks and then every 9 weeks thereafter. Treatment continued until disease progression or unacceptable toxicity. Treatment duration was 1 cycle. Response was evaluated up to 3 months. ]
   The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) outside the field of radiation based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions. 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. Incidence of Grade 4 Treatment-Related Toxicity [ Time Frame: Tumor measurements are repeated every 6 weeks for the first 24 weeks and then every 9 weeks thereafter. Treatment continued until disease progression or unacceptable toxicity. Response was evaluated up to 3 months. ]
   All grade 4 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv3 as reported on case report forms were counted. Incidence is the number of patients experiencing at least one treatment-related grade 4 AE of any type during the time of observation.
2. Median Progression-free Survival (PFS) [ Time Frame: Tumor measurements are repeated every 6 weeks for the first 24 weeks and then every 9 weeks thereafter. Treatment continued until disease progression or unacceptable toxicity. The maximum follow-up time is 3 months. ]
   Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.
3. Median Overall Survival (OS) [ Time Frame: Tumor measurements are repeated every 6 weeks for the first 24 weeks and then every 9 weeks thereafter. Treatment continued until disease progression or unacceptable toxicity. The maximum follow-up time is 13 months. ]
   OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.

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:

• Participants must have histologically or cytologically confirmed invasive breast cancer, with metastatic disease. Participants without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluation.

• Invasive disease must have been tested for ER, PR and HER2. Participants must have hormone-receptor positive, HER2-negative breast cancer defined as:

  • ER>1% or PR>1%
  • HER2-negative per ASCO CAP guidelines, 2013 [Wolff et al., 2013]
• Participant must be a candidate for palliative radiation treatment to at least one bone, lymph node, or soft tissue lesion. Radiation of visceral lesions (such as lung or hepatic lesions) is not permitted.
• Participant must have measurable disease outside the field of radiation as defined by RECIST 1.1.
• If tumor is accessible and outside the field of radiation, the participant must be willing to undergo a research biopsy at baseline and after 2 cycles of pembrolizumab. Participants for whom newly-obtained samples cannot be provided (e.g. inaccessible or safety concern) must be willing to submit an archival specimen.

• Prior systemic therapy:

  • Participant must be at least 14 days from the last dose of prior chemotherapy, endocrine therapy, biological agents (including small molecule targeted therapy) or any investigational drug product with adequate recovery of toxicity to baseline, or grade 1(with the exception of alopecia and hot flashes) at the time of registration.
  • There is no limit to the number of prior lines of therapy, including endocrine or cytotoxic agents. Systemic treatment naive patients for metastatic disease are also eligible.
  • Participants may initiate or continue bisphosphonate therapy on study.
  • Continuation of ovarian suppression is allowed.

• Prior radiation therapy:

  • Patients must be at least 3 months from prior radiation therapy
  • Re-irradiation of the same field is not allowed
• Concurrent administration of other cancer specific therapy during the course of this study is not allowed.
• The subject is ≥18 years old
• ECOG performance status ≤1 (See Appendix A for details)

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

  • absolute neutrophil count ≥1,500/mcL
  • platelets ≥100,000/mcL
  • hemoglobin ≥ 8 g/dl
  • total bilirubin ≤1.5 × institutional upper limit of normal (ULN)
  • AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN or ≤ 5 × institutional ULN for participants with documented liver metastases
  • creatinine ≤1.5 ×within normal institutional ULN (or 2.0 x ULN in patients with documented Gilbert's Syndrome) 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.
• Female subjects of childbearing potential must have a negative pregnancy test at screening
• Female and male subjects of childbearing potential must agree to use an adequate method of contraception as outlined in section 5.4.1. Contraception is required starting with the first dose of study medication through 120 days after the last dose of study medication Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
• Resolution of all chemotherapy-related or radiation-related toxicities to Grade 1 severity or lower, except for stable sensory neuropathy (≤ Grade 2) and alopecia.
• The subject is capable of understanding and complying with the protocol and has signed the informed consent document

Exclusion Criteria:

• Participants who are receiving any other investigational agents.
• Previous treatment with any anti-PD-1, PD-L1, or PD-L2 agent.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to pembrolizumab.

• 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 (whole brain radiotherapy, radiosurgery, or a combination) at least 3 months prior to trial therapy initiation,
  • are neurologically stable, and
  • have recovered from 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 prior to registration.
• Radiologic or clinical evidence of Spinal Cord Compression.
• Spinal Instability Neoplastic Score ≥ 7 unless lesion reviewed by a neurosurgical service and considered stable.
• Participants with bone lesions requiring surgical fixation to provide mechanical stability are ineligible. Participants with previously fixed lesions are allowed.
• The participant has an uncontrolled intercurrent illness, including, but not limited to uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, congestive heart failure-New York Heart Association Class III or IV, active ischemic heart disease, myocardial infarction within the previous six months, uncontrolled diabetes mellitus, gastric or duodenal ulceration diagnosed within the previous 6 months, severe malnutrition 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], eg, a repeated demonstration of a QTc interval >500 ms).
• Participant has a medical condition that requires chronic systemic steroid therapy or on any other form of immunosuppressive medication. For example, patients with autoimmune disease that requires systemic steroids or immunosuppression agents should be excluded. Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Has history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
• Has a history of interstitial lung disease.
• The participant is known to be positive for the human immunodeficiency virus (HIV), HepBsAg, or HCV RNA. HIV-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with Pembrolizumab.
• Individuals with a history of different malignancy are ineligible except for the following circumstances. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years or are deemed by the investigator to be at low risk for recurrence of that malignancy.
• Has received a live vaccine within 30 days of planned start of study therapy.
• The participant is pregnant or breast-feeding

Contacts and Locations

Locations

United States, Massachusetts

Dana-Farber Cancer Institute

Boston, Massachusetts, United States, 02215

Sponsors and Collaborators

Dana-Farber Cancer Institute

Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Sara Tolaney, MD; Dana-Farber Cancer Institute

  Study Documents (Full-Text)

Documents provided by Sara Tolaney, Dana-Farber Cancer Institute:

Study Protocol and Statistical Analysis Plan  [PDF] April 9, 2019

More Information

Publications of Results:

Barroso-Sousa R, Krop IE, Trippa L, Tan-Wasielewski Z, Li T, Osmani W, Andrews C, Dillon D, Richardson ET 3rd, Pastorello RG, Winer EP, Mittendorf EA, Bellon JR, Schoenfeld JD, Tolaney SM. A Phase II Study of Pembrolizumab in Combination With Palliative Radiotherapy for Hormone Receptor-positive Metastatic Breast Cancer. Clin Breast Cancer. 2020 Jun;20(3):238-245. doi: 10.1016/j.clbc.2020.01.012. Epub 2020 Jan 30.

• Responsible Party: Sara Tolaney, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT03051672
• Other Study ID Numbers: 16-588
• First Posted: February 14, 2017
• Results First Posted: April 27, 2021
• Last Update Posted: April 27, 2021
• Last Verified: March 2021

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 Sara Tolaney, Dana-Farber Cancer Institute:

Breast Cancer

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents