Clinical Trials /

Avelumab in Patients With MSS, MSI-H and POLE-mutated Recurrent or Persistent Endometrial Cancer and of Avelumab/Talazoparib and Avelumab/Axitinib in Patients With MSS Recurrent or Persistent Endometrial Cancer

NCT02912572

Description:

This research study is evaluating a drug called Avelumab alone and in combination with Talazoparib or Axitinib as a possible treatment for recurrent or metastatic endometrial cancer.

Related Conditions:
  • Endometrial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Avelumab in Patients With MSS, MSI-H and POLE-mutated Recurrent or Persistent Endometrial Cancer and of Avelumab/Talazoparib and Avelumab/Axitinib in Patients With MSS Recurrent or Persistent Endometrial Cancer
  • Official Title: A Phase 2, Two-Group, Two-Stage, Open-Label Study of Avelumab in Patients With MSS, MSI-H and POLE-mutated Recurrent or Persistent Endometrial Cancer, Avelumab / Talazoparib in Patients With MSS Recurrent or Persistent Endometrial Cancer, and Avelumab / Axitinib in Patients With MSS Recurrent or Persistent Endometrial Cancer

Clinical Trial IDs

  • ORG STUDY ID: 16-322
  • NCT ID: NCT02912572

Conditions

  • Metastatic Endometrial Cancer

Interventions

DrugSynonymsArms
AvelumabMSS Avelumab/Axitinib Combination Arm
TalazoparibMSS Avelumab/Talazoparib Combination Arm
AxitinibMSS Avelumab/Axitinib Combination Arm

Purpose

This research study is evaluating a drug called Avelumab alone and in combination with Talazoparib or Axitinib as a possible treatment for recurrent or metastatic endometrial cancer.

Detailed Description

      This research study is a Phase II clinical trial. Phase II clinical trials test the
      effectiveness of an investigational drug to learn whether the drug works in treating a
      specific cancer. "Investigational" means that the drug is still being studied and that
      research doctors are trying to find out more about it-such as the safest dose to use, the
      side effects it may cause, and if the drug is effective for treating different types of
      cancer. It also means that the FDA (the U.S. Food and Drug Administration) has not yet
      approved the drug for use in patients, including people with Metastatic Endometrial Cancer.

      Avelumab is a drug that may stop cancer cells from growing by enabling the activation of the
      immune system. Avelumab blocks an immune inhibiting signal that can impair the ability of the
      immune system to attack cancers.

      Talazoparib is a drug that stops the activity of a protein (called PARP) that's involved in
      repairing damage to the DNA within your cells. When PARP is turned off by Talazoparib in
      cancer cells, DNA damage cannot be repaired and leads to the death of the cancer cells.

      Axitinib is a drug that may stop cancer cells from growing by blocking certain proteins that
      cancer cells use to form new blood vessels, which the cancer needs in order to grow.

      In this research study, the investigators are looking to see whether Avelumab, the
      combination of Avelumab and Talazoparib, or the combination of Avelumab and Axitinib are
      effective in treating recurrent and Metastatic Endometrial Cancer.

      Additionally, the investigators are looking to see if participants whose tumors contain a
      particular genetic make-up will have better response to Avelumab, the combination of Avelumab
      and Talazoparib, or the combination of Avelumab and Axitinib.
    

Trial Arms

NameTypeDescriptionInterventions
Pole Mutated Endometrial CancerExperimentalParticipants with Pole mutated endometrial cancer Avelumab will be administered intravenously twice per cycle
  • Avelumab
MSS Endometrial CancerExperimentalParticipants with MSS mutated endometrial cancer Avelumab will be administered intravenously twice per cycle
  • Avelumab
MSS Avelumab/Talazoparib Combination ArmExperimentalParticipants with MSS mutated endometrial cancer Avelumab will be administered intravenously twice per cycle Talazoparib will be administered one time per day by mouth
  • Avelumab
  • Talazoparib
MSS Avelumab/Axitinib Combination ArmExperimentalParticipants with MSS mutated endometrial cancer Avelumab will be administered intravenously twice per cycle Axitinib will be administered twice per day by mouth
  • Avelumab
  • Axitinib

Eligibility Criteria

        Inclusion Criteria:

        Participants must be classified into one of the following cohorts of recurrent or
        persistent endometrial cancer of any histology:

        The MSI/POLE cohort includes endometrial cancers that are:

        --MSI-H as determined by immunohistochemical complete loss of expression (absence of
        nuclear immunoreactivity) of at least one of the mismatch repair genes MSH2, MSH6, MLH1 and
        PMS2. This test is now done routinely for every newly diagnosed endometrial cancer patient
        in most centers in the US.

        And/OR:

        --POLE-mutated, i.e. endometrial cancers known to harbor mutations in the exonuclease
        domain (amino acid residues 268-471) of polymerase e (POLE) as determined by targeted
        sequencing or other next generation sequencing assay. Any Clinical Laboratory Improvement
        Amendments (CLIA)-approved genomic test documenting mutations in the exonuclease domain of
        POLE gene (amino acid residues 268-471) in the tumor will be accepted as proof of presence
        of POLE mutations and will lead to classification into this patient cohort.

        The MSS cohorts include:

          -  Endometrial cancers that are MSS as determined by normal immunohistochemical nuclear
             expression of all the mismatch repair genes MSH2, MSH6, MLH1 and PMS2. Tumors which
             have not been sequenced for POLE mutations (i.e. their POLE mutations status is
             unknown) but are MSS, will be included in this cohort.

               -  All patients must have measurable disease as defined by RECIST 1.1. Measurable
                  disease is defined as at least one lesion that can be accurately measured in at
                  least one dimension (longest diameter to be recorded). Each lesion must be >= 10
                  mm when measured by CT, MRI or caliper measurement by clinical exam; or >= 20 mm
                  when measured by chest x-ray. Lymph nodes must be > 15 mm in short axis when
                  measured by CT or MRI.

               -  Prior Therapy:

          -  There is no upper limit of prior therapies but patients must have had one prior
             chemotherapeutic regimen for management of endometrial carcinoma. Initial treatment
             may include chemotherapy, chemotherapy and radiation therapy, and/or
             consolidation/maintenance therapy. Any platinum based chemotherapy (single agent
             platinum or any platinum doublet) administered in conjunction with primary radiation
             as a radio-sensitizer WILL be counted as a systemic chemotherapy regimen. Furthermore,
             patients who have only received chemotherapy in the adjuvant setting will be eligible
             for the study.

          -  Prior hormonal therapy is allowed.

          -  Patients must NOT have received any class of drugs targeted to the PD-1/PD-L1 pathway.

          -  Patients must NOT have received any prior PARP inhibitor therapy (for patients being
             considered for the avelumab/talazoparib cohort only).

          -  Patients must NOT have received prior axitinib (for patients being considered for the
             avelumab/axitinib cohort only).

               -  Age of 18 or greater years. Because insufficient dosing or adverse event data are
                  currently available on the use of Avelumab, talazoparib, and/or axitinib in
                  participants < 18 years of age, children are excluded from the study. Endometrial
                  cancer is very rare in the pediatric population.

               -  ECOG performance status 0 or 1 (reference Appendix A for ECOG performance status
                  criteria).

               -  Availability of a formalin fixed paraffin embedded (FFPE) block of cancer tissue
                  OR 15 unstained 5-micron slides from the original surgery or biopsy or from a
                  biopsy of recurrent disease.

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

          -  absolute neutrophil count >1,500/mcL

          -  platelets >100,000/mcL

          -  hemoglobin ≥ 9g/dL

          -  total bilirubin within normal institutional limits

          -  AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal

          -  creatinine within normal institutional limits OR

          -  creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels above
             institutional normal.

        Please note: creatinine clearance (CLCR) should be estimated according to the
        Cockcroft-Gault formula as:

        CLCR={[(140-age) × weight)]/(72 x SCR)} × 0.85 where CLCR (creatinine clearance) is
        measured in mL/min, age is expressed in years, weight in kilograms (kg), and SCR (serum
        creatinine) in mg/dL.

        NOTE: Patients with moderate renal impairment (defined as an estimated creatinine clearance
        of 30-59 mL/min) will receive a reduced starting dose of Talazoparib at 0.75 mg PO QD.

          -  Participant must not be pregnant or breastfeeding given that avelumab is an agent with
             unknown effects in pregnancy and breastfeeding and the potential for teratogenesis.
             Females of childbearing potential are defined as those who are not surgically sterile
             (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or
             post-menopausal (defined as ≥ 12 months with no menses without an alternative medical
             cause). Serum pregnancy test (for females of childbearing potential) negative at
             screening.

          -  The effects of avelumab on the developing human fetus are unknown. For this reason and
             because some immunomodulatory agents are known to be teratogenic, women of
             child-bearing potential must agree to use adequate contraception (hormonal or barrier
             method of birth control; abstinence) prior to study entry and for the duration of
             study participation. Should a woman become pregnant or suspect she is pregnant while
             she or her partner is participating in this study, she should inform her treating
             physician immediately.

          -  Toxicities of prior therapy (excepting alopecia and sensory neuropathy) should be
             resolved to < grade 2 per the revised NCI Common Terminology Criteria for Adverse
             Events (CTCAE) version 4. All appropriate treatment areas should have access to a copy
             of the CTCAE version 4. A copy of the CTCAE version 4 can be downloaded from the CTEP
             website at: http://ctep.cancer.gov.

          -  Ability to understand and the willingness to sign a written informed consent document.

        Additional inclusion criteria for the avelumab/axitinib cohort:

          -  Participants must have adequately controlled blood pressure (BP) with or without
             antihypertensive medications, defined as systolic BP that must be ≤140 mmHg and
             diastolic BP that must be ≤90 mmHg on two separate BP readings taken at least 1 hour
             apart at screening.

          -  Participants must have LVEF ≥ lower limit of normal (LLN) as assessed by either
             multigated acquisition (MUGA) scan or echocardiogram (ECHO).

        Exclusion Criteria:

          -  Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
             nitrosoureas or mitomycin C) prior to entering the study or those who have not
             recovered from adverse events due to agents administered more than 4 weeks earlier.

          -  Participants who are receiving any other investigational agents.

          -  Participants with known brain metastases should be excluded from this clinical trial
             because of their poor prognosis and because they often develop progressive neurologic
             dysfunction that would confound the evaluation of neurologic and other adverse events.

          -  History of allergic reactions attributed to avelumab or any component in its
             formulations, or compounds of similar chemical or biologic composition to avelumab.
             Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI CTCAE
             v 4.03), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more
             features of partially controlled asthma)

          -  Participants with a history of treatment with an anti-PD-1, anti-PD-L1, anti-CTLA-4 or
             other investigational agents that target immune checkpoint inhibitors.

          -  Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)
             related illness, which may compromise the efficacy of immunostimulatory therapy.

          -  Positive test for HBV surface antigen

          -  Positive Hepatitis C antibody and positive confirmatory HCV RNA test. The confirmatory
             HCV RNA test is not required if the HCV antibody is negative. If Hepatitis C antibody
             is positive, the confirmatory HCV RNA test should be done and if it is negative, then
             participants are eligible.

          -  Subjects requiring hormone replacement with corticosteroids are eligible if the
             steroids are administered only for the purpose of hormonal replacement and at doses ≤
             10 mg or 10 mg equivalent prednisone per day

          -  Active infection requiring systemic therapy.

          -  Current or prior use of immunosuppressive medication within 7 days prior to enrollment
             with the following exceptions to this exclusion criterion:

               -  Intranasal, inhaled, topical steroids, or local steroid injections (eg,
                  intra-articular injection);

               -  Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
                  prednisone or equivalent;

               -  Steroids as premedication for hypersensitivity reactions (eg, CT scan
                  premedication).

          -  Active autoimmune disease that might deteriorate when receiving an immunostimulatory
             agent. Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid
             disease not requiring immunosuppressive treatment are eligible.

          -  Prior organ transplantation including allogeneic stem-cell transplantation.

          -  Severe gastrointestinal conditions such as clinical or radiological evidence of bowel
             obstruction within 4 weeks prior to study entry, uncontrolled diarrhea in the last 4
             weeks prior to enrollment, or history of inflammatory bowel disease.

          -  Uncontrolled intercurrent illness including, but not limited to symptomatic congestive
             heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric
             illness/social situations that would limit compliance with study requirements.

          -  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.

          -  Known alcohol or drug abuse.

          -  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 5 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.

          -  All other significant diseases (for example, inflammatory bowel disease, uncontrolled
             asthma), which, in the opinion of the Investigator, might impair the subject's
             tolerance of trial treatment.

          -  Any psychiatric condition that would prohibit the understanding or rendering of
             informed consent

          -  Vaccination within 4 weeks of the first dose of avelumab and while on trial is
             prohibited except for administration of inactivated vaccines.

          -  Patients may not use natural herbal products or other "folk remedies" while
             participating in this study. Herbal medications include, but are not limited to St.
             John's Wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA),
             yohimbe, saw palmetto, and ginseng.

        Additional exclusion criteria for the avelumab/axitinib cohort:

          -  Participants having >1+ proteinuria on urinalysis or UPCR >1 will undergo a 24-hour
             urine collection for quantitative assessment of proteinuria. Participants with urine
             protein >1 g/24-hours will be ineligible.

          -  Participants with concern for bowel or serosal involvement will be ineligible, due to
             the risk of perforation or fistulization with anti-angiogenic agents.

          -  Participants will be ineligible if they have active gastrointestinal bleeding, as
             evidenced by clinically significant hematemesis, hematochezia, or melena in the past 3
             months without evidence of resolution documented by endoscopy or colonoscopy.

          -  Participants will be ineligible if using anticoagulant therapy with oral vitamin K
             antagonists, novel oral anticoagulants (NOACs), or direct oral anticoagulants (DOACs),
             inclusive of direct thrombin inhibitors and direct factor Xa inhibitors. Therapeutic
             use of low molecular weight heparin is allowed. Low dose heparin required for
             maintenance of patency of central venous access devices are allowed.

          -  Grade ≥3 hemorrhage within 4 weeks preceding Cycle 1 Day 1 treatment.

          -  Ongoing cardiac dysrhythmias of 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 to be
             either:

               -  Strong CYP3A4/5 inhibitors, including administration within 10 days prior to
                  Cycle 1 Day 1 treatment, including but not limited to grapefruit juice,
                  grapefruit-related fruits (Seville oranges, pomelos), ketoconazole, miconazole,
                  itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin,
                  indinavir, saquinavir, ritonavir, nelfinavir, amprenavir, fosamprenavir
                  nefazodone, lopinavir, troleandomycin, mibefradil, conivaptan. The topical use of
                  these medications is allowed if systemic absorption is considered minimal.

               -  Strong CYP3A4/5 inducers, including administration within 10 days prior to Cycle
                  1 Day 1 treatment, including but not limited to phenobarbital, rifampin,
                  phenytoin, carbamazepine, rifabutin, rifapentine, clevidipine, St. John's wort.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Activity Of Avelumab and Avelumab plus Talazoparib In Patients With Recurrent Or Persistent Endometrial Cancer
Time Frame:2 years
Safety Issue:
Description:As assessed by the frequency of patients who survive progression-free for at least 6 months (PFS6) after initiating therapy or have objective tumor response

Secondary Outcome Measures

Measure:Duration of Progression Free Survival as Assessed by RECIST 1.1
Time Frame:2 years
Safety Issue:
Description:RECIST - Response Evaluation Criteria in Solid Tumors
Measure:Duration of Overall Survival
Time Frame:2 years
Safety Issue:
Description:
Measure:Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0
Time Frame:2 years
Safety Issue:
Description:As classified by the common terminology criteria for adverse events (CTCAE) version 4.0
Measure:Immune-Related Objective Response
Time Frame:2 years
Safety Issue:
Description:as assessed by immune-related RECIST (irRECIST)
Measure:Immune-Related Progression-Free Survival (irPFS)
Time Frame:2 years
Safety Issue:
Description:Defined as time from cohort assignment to death or to immunie-related progression of disease (irPD)
Measure:Clinical Activity of Combination Avelumab/Axitinib
Time Frame:2 years
Safety Issue:
Description:As measured by median progression-free survival (PFS) and median overall survival (OS); by the immune-related ORR, as measured by irRECIST criteria; and by the immune-related PFS (irPFS);
Measure:Number of Participants Receiving Avelumab/Axitinib With Treatment-Related Adverse Events as Assessed by CTCAE v4.1
Time Frame:2 years
Safety Issue:
Description:As classified by the common terminology criteria for adverse events (CTCAE) version 4.1

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Endometrial Cancer

Last Updated

June 1, 2020