Pembrolizumab With Axitinib in Recurrent Endometrial Cancer

November 4, 2020 updated by: Case Comprehensive Cancer Center

Pembrolizumab With Axitinib in Recurrent Endometrial Cancer With Deficient Mismatch Repair System Post PD1 Exposure: Phase II Trial

The main purpose of this study is to see if adding the experimental medication, axitinib, to usual treatment with pembrolizumab will work better than pembrolizumab alone. The study team will look at overall safety and side effects of the combination of axitinib and pembrolizumab to see how well it is tolerated. Researchers will also want to take some research blood samples to explore what effects the combination of treatment has on participants' cells and immune system and to see if there are things in participants' blood that can predict a response or resistance to the combined treatment.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

This is a Phase 2, open label study of pembrolizumab in combination with axitinib in adult women with recurrent endometrial cancer with deficient mismatch repair system. Twenty-six participants in total will be enrolled into the study. All participants enrolled will receive pembrolizumab as standard of care combined with axitinib.

Axitinib is approved by the Food and Drug Administration (FDA) for treatment in certain participants with advanced renal cell cancer but is considered investigational (experimental) in this study. However, it is not FDA approved for recurrent endometrial cancer. Axitinib is a type of drug called a tyrosine kinase inhibitor. It is thought to work by blocking tumor vasculature and decreasing the blood supply to the tumor. Also it has been shown to improve the function of immune cells within the tumor which may enable them to kill the tumor.

Pembrolizumab is an immunotherapy that is FDA approved to treat participants with recurrent endometrial cancer with deficient mismatch repair system (dMMR). dMMR means having genetic changes within the tumor that make it unstable and potentially able to benefit from immunotherapy. Pembrolizumab works by improving the function of the immune cells enabling them to kill cancer cells.

Axitinib given in combination with pembrolizumab has not been tested for endometrial cancer. In this study the combination of axitinib and pembrolizumab is experimental because it is not approved by the Food and Drug Administration (FDA).

Study Type

Interventional

Phase

  • Phase 2

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

19 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • Subjects must have recurrent endometrial cancer with deficient mismatch repair system. Mismatch repair deficiency is defined by 1. Immunohistochemistry with loss of expression of one of these proteins in tumor tissue as defined by standard of care: MLH1, MSH2, MSH6 and PMS2, 2. Microstaellite (MSI) unstable by PCR per standard of care, 3. MSI high by next generation sequencing using commercial platform specifically CARIS, TEMPUS or Foundation testing.
  • Subjects must have histologically confirmed endometrioid, clear cell, high grade serous, undifferentiated carcinoma or mixed histology.
  • Must have had prior therapy with a PD1 inhibitor, pembrolizumab.
  • Up to 5 prior lines of therapy are allowed.
  • Prior anti-angiogenesis therapy is not allowed. Bevacizumab if given with chemotherapy in primary or adjuvant setting is allowed if treatment-free interval exceeded 6 months.
  • Subjects must have measurable disease based on RECIST 1.1 with at least one target lesion.
  • Subjects must have an ECOG performance status of 0-1.

  • Subjects must have normal organ and marrow function as defined below within 14 days of enrollment unless otherwise indicated:

    • Hemoglobin ≥ 9.0 g/dl (may have been transfused)
    • Absolute neutrophil count ≥ 1,500/mcL
    • Platelet count ≥ 100,000/mcL
    • Total bilirubin ≤ 1.5 x the upper limit of normal (ULN) range
    • AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN orAST and ALT levels ≤ 5 x ULN (for subjects with documented metastatic disease to the liver).
    • Estimated Creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method)
    • TSH within normal institutional limits. If elevated, patient can be eligible if evaluated by an endocrine specialist, placed on replacement therapy and deemed eligible with no current or prior autoimmune disease.
  • Subjects must have the ability to understand and the willingness to sign a written informed consent document.
  • Negative serum or urine pregnancy test at screening for women of childbearing potential.
  • Willing to use highly effective contraception throughout the study and for at least 30 days after last treatment administration if childbearing potential exists
  • Availability of an archival FFPE tumor tissue block from primary diagnosis specimen, metastatic, or recurrent site. If an FFPE tissue block cannot be provided then 15 unstained slides (10 minimum) will be acceptable. Please refer to the laboratory manual for complete details.
  • Urinary protein <2+ by urine dipstick. If dipstick is >2+, then 24-hour urinary protein <2 g per 24 hours is required.
  • No evidence of uncontrolled hypertension as documented by 2 baseline blood pressure (BP) readings taken at least 1 hour apart whether same visit or different visits. The baseline systolic BP readings must be <140 mm Hg, and the baseline diastolic BP readings must be <90 mm Hg. The use of antihypertensive medications to control BP is allowed.

Exclusion Criteria:

  • Patients with sarcoma or carcinosarcoma
  • Mismatch repair proficient tumors
  • Patients with primary platinum refractory cancer defined as progressing during or within 3 months of completing primary platinum therapy.
  • Prior anti-cancer therapy within 3 weeks prior to study enrollment.
  • Known symptomatic brain metastases requiring steroids. Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study enrollment, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable.
  • Patients having received prior therapy with PD1 or PDL1 or CTLA4 inhibitors or other immunotherapeutic agents except pembrolizumab.
  • Patients having received prior anti-VEGF therapy as explained above
  • Bowel obstruction (with or without gastrostomy tube) or inability to take oral medications
  • Patients with a prior or current bowel perforation or fistula
  • Uncontrolled hypertension defined as 140/90 or greater despite medical management with multiple medications
  • ECOG performance >1
  • Active autoimmune disease that might deteriorate when receiving an immune-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.

  • Patients currently on immunosuppressive therapy except:

    • Intra-nasal, inhaled, topical or local steroid injections (e.g., intra-articular injection)
    • Steroids as premedication for hypersensitivity reaction (e.g., CT scan premedication)."
    • Systemic corticosteroids at physiologic doses not exceeding 10 mg/day of prednisone or equivalent
  • Patients who are pregnant or breast feeding.
  • Known history of testing positive for HIV or known acquired immunodeficiency syndrome.
  • Known history of immune-mediated colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis.
  • Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
  • Individuals with a history of a 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 and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: breast cancer in situ, cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.
  • Prior organ transplantation including allogenic stem-cell transplantation.
  • Active infection requiring intravenous systemic therapy.
  • Known hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)
  • Vaccination within 4 weeks of the first dose of treatment and while on trials is prohibited except for administration of inactivated vaccines.
  • Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v5 Grade ≥ 3)"
  • Persistent toxicity related to prior therapy (NCI CTCAE v. 5 Grade > 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator's judgment are acceptable.
  • Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

  • Gastrointestinal abnormalities including:

    • Inability to take oral medication;
    • Requirement for intravenous alimentation;
    • Treatment for active peptic ulcer disease in the past 6 months;
    • Active gastrointestinal bleeding, unrelated to cancer, as evidenced by clinically significant hematemesis, hematochezia or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy;
    • Malabsorption syndromes.
  • Requirement of anticoagulant therapy with oral vitamin K antagonists. Low-dose anticoagulants for maintenance of patency of central venous access device or prevention of deep venous thrombosis is allowed. Therapeutic use of low molecular weight heparin is allowed.
  • Evidence of inadequate wound healing.
  • Grade >3 hemorrhage within 4 weeks of patient enrollment.
  • Evidence of tumor involvement of the myocardium or pericardium or tumor thrombus extending to the heart.
  • Ongoing known cardiac dysrhythmias of NCI CTCAE Grade >2 or prolongation of the QTc interval to >500 msec.
  • Current use or anticipated need for treatment with drugs or foods that are known strong CYP3A4/5 inhibitors, including their administration within 10 days prior to patient enrollment (eg, grapefruit juice or grapefruit/grapefruit-related citrus fruits [eg, Seville oranges, pomelos], ketoconazole, miconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, indinavir, saquinavir, ritonavir, nelfinavir, amprenavir, fosamprenavir nefazodone, lopinavir, troleandomycin, mibefradil, and conivaptan). The topical use of these medications (if applicable), such as 2% ketoconazole cream, is allowed.
  • Current use or anticipated need for drugs that are known strong CYP3A4/5 inducers, including their administration within 10 days prior to patient enrollment, eg, phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentin, clevidipine, St John's wort.

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: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Pembrolizumab & axitinib
All participants enrolled will receive pembrolizumab as standard of care (SOC) combined with axitinib. Axitinib will be self-administered orally twice daily at 5 mg. On days when both drugs are administered, axitinib will be administered first, followed by pembrolizumab. Treatment will continue until disease progression or unacceptable grade 3/4 toxicities. For patients with a complete response to therapy, maintenance therapy with both drugs will be continued for 12 months.
Drug: Pembrolizumab
200 mg IV day 1 of each cycle every 21 days
Drug: Axitinib
5 mg PO BID continuously

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Objective response rate (ORR) at 12 weeks by RECIST 1.1
Time Frame: Up to 12 weeks from start of treatment

Percent of participants with ORR, defined as those having either a partial or complete response (according to RECIST 1.1) per investigator determination at 12 weeks from the date of study enrollment.

Complete response (CR): Disappearance of all target lesions

Partial response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD
Up to 12 weeks from start of treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Average overall Survival (OS)
Time Frame: Assessed up to 60 months
Average number in months from the date of study enrollment to the date of death (any cause) or last known date of follow up if otherwise lost to follow up.
Assessed up to 60 months
Clinical benefit rate
Time Frame: Up to 12 weeks from start of treatment
Clinical benefit, defined by percent of participants with ORR and stable disease at 12 weeks
Up to 12 weeks from start of treatment
Number of participants with grade 3 and 4 immune and non-immune related toxicities assessed via NCI CTCAE v.5.03
Time Frame: 90 days from end of treatment
Number of participants with grade 3 and 4 immune and non-immune related toxicities assessed via National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.5.03
90 days from end of treatment
Average progression-free survival (PFS)
Time Frame: 12 months from end of treatment
Average number of months from the date of study enrollment to the date of an event of disease progression (according to RECIST 1.1) per investigator determination or to the date of death (any cause).
12 months from end of treatment

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Translational endpoints
Time Frame: 12 months from end of treatment
Translational markers to predict resistance and response to therapy. Identify genomic, immune related markers that can predict response and/or resistance to the combined therapy.
12 months from end of treatment

Collaborators and Investigators

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

Sponsor

Case Comprehensive Cancer Center

Investigators

  • Principal Investigator: Haider Mahdi, MD, Cleveland Clinic Women's Health Institute

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

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 (Anticipated)

February 1, 2021

Primary Completion (Anticipated)

January 1, 2025

Study Completion (Anticipated)

December 1, 2026

Study Registration Dates

First Submitted

October 16, 2019

First Submitted That Met QC Criteria

December 10, 2019

First Posted (Actual)

December 13, 2019

Study Record Updates

Last Update Posted (Actual)

November 5, 2020

Last Update Submitted That Met QC Criteria

November 4, 2020

Last Verified

November 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CASE4819

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

IPD Plan Description

This is a single institution study and the IPD data are not planned to be shared outside the institution.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

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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