Clinical Trials /

The EndoBARR Trial (Endometrial Bevacizumab, Atezolizumab, Rucaparib)

NCT03694262

Description:

To demonstrate the efficacy and safety of the combination of rucaparib, bevacizumab and atezolizumab in recurrent, progressive endometrial carcinoma.

Related Conditions:
  • Endometrial Adenocarcinoma
  • Endometrial Clear Cell Adenocarcinoma
  • Endometrial Endometrioid Adenocarcinoma
  • Endometrial Mixed Adenocarcinoma
  • Endometrial Mucinous Adenocarcinoma
  • Endometrial Serous Adenocarcinoma
  • Endometrial Squamous Cell Carcinoma
  • Endometrial Transitional Cell Carcinoma
  • Endometrial Undifferentiated Carcinoma
  • Uterine Carcinosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: The EndoBARR Trial (Endometrial Bevacizumab, Atezolizumab, Rucaparib)
  • Official Title: An Open Label, Non-Randomized Multisite Phase II Trial Combining Bevacizumab, Atezolizumab and Rucaparib for the Treatment of Previously Treated Recurrent and Progressive Endometrial Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: PRO
  • NCT ID: NCT03694262

Conditions

  • Endometrial Cancer

Interventions

DrugSynonymsArms
RucaparibRubracaTreatment
BevacizumabAvastinTreatment
AtezolizumabTecentriqTreatment

Purpose

To demonstrate the efficacy and safety of the combination of rucaparib, bevacizumab and atezolizumab in recurrent, progressive endometrial carcinoma.

Detailed Description

      The combination of the three proposed agents offers the opportunity to explore synergistic
      relationships between antiangiogenic and immunotherapy and antiangiogenic and PARPi.
      Increasing genetic instability by PARPi and double-strand breaks may lead to a
      proinflammatory state that would enhance the activity of immunotherapy, leading to
      synergistic response in a category of solid tumors that lack active therapy. It is expected
      that increased double-strand breaks may lead to increased expression of immunogenic antigens,
      increasing the effect of anti-PD-L1 therapy. Phase I data combining the PD-L1 inhibitor
      durvalamab with either olaparib or cediranib showed good tolerability and evidence of
      response.
    

Trial Arms

NameTypeDescriptionInterventions
TreatmentExperimentalCycle length = 21 days Atezolizumab 1,200mg IV on day 1 Bevacizumab 15mg/kg IV on day 1 Rucaparib 600mg orally twice daily by continuous dosing
  • Rucaparib
  • Bevacizumab
  • Atezolizumab

Eligibility Criteria

        Inclusion Criteria:

          1. Patients must have recurrent or persistent/progressive endometrial carcinoma, which is
             refractory to curative therapy or established treatments. Histologic confirmation of
             the original primary tumor is required. Stained slides of either the primary or
             recurrent tumor are required. If primary FFPE samples are not available, a biopsy
             demonstrating recurrent disease must be obtained. Pathologic Slides/Blocks will be
             reviewed at the primary site for confirmation.

          2. Patients with the following histologic epithelial cell types are eligible:
             Endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear
             cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise
             specified (N.O.S.), mucinous adenocarcinoma, squamous cell carcinoma, transitional
             cell carcinoma and uterine carcinosarcoma (MMT).

          3. Patients must have had one prior chemotherapeutic regimen for management of
             endometrial carcinoma. Chemotherapy administered in conjunction with primary radiation
             as a radio-sensitizer WILL be counted as a chemotherapy regimen. Patients may have
             had, but are not required to have received, a second chemotherapeutic regimen for
             recurrent disease.

          4. 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 target lesion must be ≥ 10 mm
             when measured by

             CT or MRI. Lymph nodes must be > 15 mm in short axis when measured by CT or MRI.

          5. Patients may be enrolled if they do not have a target lesion (>= 10 mm lesion or >=15
             mm lymph node), if they have measurable disease. This is defined by RECIST 1.1 as a
             suspicious lesion <10mm or a lymph node >=10mm but <15mm.

          6. Patients must have an EGOG Performance Status of 0, 1.

          7. Recovery from effects of recent surgery, radiotherapy, or chemotherapy

          8. Patients should be free of active infection requiring antibiotics (with the exception
             of uncomplicated UTI).

          9. Any hormonal therapy directed at the malignant tumor must be discontinued at least one
             week prior to registration.

         10. Any other prior therapy directed at the malignant tumor, including chemotherapy and
             immunologic agents, must be discontinued at least three weeks prior to first cycle of
             treatment.

         11. Any prior radiation therapy must be completed at least four weeks prior to first cycle
             of treatment.

         12. Prior hormonal therapy is allowed. There is no limit on the number of prior hormonal
             therapies allowed. Hormonal therapy will not be counted as a line of therapy for
             purposes of this trial.

         13. Patients must have a urine protein of 2+ on dipstick. If dipstick is >2+, 24-hour
             urine protein must be obtained and should be < 1g for patient to be eligible.

         14. Patients must have signed an approved informed consent and authorization permitting
             release of personal health information for study purposes.

         15. Patients must meet pre-entry requirements, as specified in section 5.

         16. Patients of childbearing potential must agree to use an accepted and effective
             nonhormonal method of contraception i.e., double-barrier method (e.g., condom plus
             diaphragm) from the time of signing the informed consent through six months after last
             dose of study drug.

         17. Patients 18 years of age or greater.

         18. Be willing to provide tissue from the primary surgical resection (paraffin block).

         19. Must have laboratory values in the below ranges:

        System Laboratory Value Endocrine Thyroid function testing (TSH) 0.350 - 5.500 ulU/mL (Or
        within institutional labarotory range).

        Free T4/Total T3 If TSH is outside of laboratory range and subject is clinically euthyroid,
        enrollment may occur if Free T4/Total T3 are in normal range by local lab values
        Hematological

        System Laboratory Value Absolute neutrophil count (ANC) ≥1,500 /mcL Platelets ≥100,000 /
        mcL Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days
        of assessment) Renal Serum creatinine OR Measured or calculateda creatinine clearance (GFR
        can also be used in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR

        ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN Hepatic Serum total
        bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels >
        1.5 ULN AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR

        ≤ 5 X ULN for subjects with liver metastases Albumin >2.5 mg/dL Coagulation International
        Normalized Ratio (INR) or Prothrombin Time (PT)

        Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving
        anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of
        anticoagulants

        ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within
        therapeutic range of intended use of anticoagulants aCreatinine clearance should be
        calculated per institutional standard.

        4.2 Exclusion Criteria

          1. Patients with a history of other invasive malignancies, with the exception of
             non-melanoma skin cancer, are excluded if there is any evidence of the other
             malignancy being present within the last two years. Patients with Ductal Carcinoma in
             situ (DCIS) of the breast in the prior two years may be enrolled on study if the
             treatment required no chemotherapy or radiation. Patients are also excluded if their
             previous cancer treatment contraindicates this protocol therapy.

          2. Patients must not have had exposure to Bevacizumab, PARPi, or immunotherapy. Patients
             may have had exposure to anti-angiogentic therapy provided it was not Bevacizumab.

          3. Patients who have received prior radiotherapy to any portion of the abdominal cavity
             or pelvis OTHER THAN for the treatment of endometrial cancer within the last three
             years are excluded. Prior radiation for localized cancer of the breast, head and neck
             or skin is permitted, provided that it was completed more than three years prior to
             registration, and the patient remains free of recurrent or metastatic disease.

          4. Patients who have received prior chemotherapy for any abdominal or pelvic tumor OTHER
             THAN for the treatment of endometrial cancer within the last three years are excluded.
             Patients may have received prior adjuvant chemotherapy for localized breast cancer,
             provided that it was completed more than two years prior to registration, and that the
             patient remains free of recurrent or metastatic disease.

          5. Inability to tolerate an oral medication or keep pills down.

          6. Patients who are pregnant or nursing.

          7. Patients with a complete bowel obstruction; recent (within six months) history of
             fistula, intraabdominal abscess or bowel perforation; subjects requiring total
             parenteral nutrition or parenteral hydration.

          8. Has a current diagnosis of immunodeficiency or is receiving systemic steroid therapy
             or any other form of immunosuppressive therapy within seven days prior to the first
             dose of trial treatment.

          9. Patients with history or evidence upon physical examination of CNS disease, including
             brain tumor, seizures not controlled with standard medical therapy or any brain
             metastases.

         10. Patients with clinically significant cardiovascular disease. This includes:

               -  Myocardial infarction or unstable angina within 12 months of the first date of
                  study treatment.

               -  New York Heart Association (NYHA) Class II or greater congestive heart failure
                  (Appendix I).

               -  History of serious ventricular arrhythmia (i.e., ventricular tachycardia or
                  ventricular fibrillation) or cardiac arrhythmias requiring antiarrhythmic
                  medications (except for atrial fibrillation that is well controlled with
                  antiarrhythmic medication).

               -  Grade 2 or greater peripheral vascular disease.

               -  Cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or
                  subarachnoid hemorrhage within six months of the first date of study treatment.

               -  History of arterial ischemia or thrombus.

         11. Patients with uncontrolled hypertension defined as systolic > 150 mm Hg or diastolic >
             90 mm Hg. The use of antihypertensive medications to control hypertension is
             permitted.

         12. Patients who have undergone major surgical procedure, open biopsy or significant
             traumatic injury within 28 days prior to the first date of study treatment or who have
             a major surgical procedure anticipated during the course of the study. Laparoscopic
             biopsy is acceptable and will not require a delay in study treatment.

         13. Patients with serious nonhealing wound, ulcer (including gastrointestinal) or bone
             fracture.

         14. Patients with any condition, which in the investigator's opinion, makes the patient
             unsuitable for study participation.

         15. Patients not available for follow-up assessments.

         16. Patients with known sensitivity to any of the products to be administered during
             dosing.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate
Time Frame:30-36 months
Safety Issue:
Description:To estimate the overall response rate (ORR) of patients with progressive/persistent or recurrent endometrial cancer on study-directed therapy, using the combination of rucaparib, bevacizumab and atezolizumab.

Secondary Outcome Measures

Measure:Progression Free Survival
Time Frame:48-60 months
Safety Issue:
Description:Progression-Free Survival (PFS) is defined as the duration of time from date of study entry to time of progression or death, whichever occurs first. The outcome is to estimate the progression free survival (PFS) of patients with progressive/persistent or recurrent endometrial cancer when treated with the combination of rucaparib, bevacizumab and atezolizumab.
Measure:Number of participants with treatment-related adverse events as assessed by CTCAE V5.0
Time Frame:30-36 months
Safety Issue:
Description:To determine the nature and degree of toxicity of treatment using the CTCAE v5.0 with this combination in this cohort of patients.
Measure:Overall Survival
Time Frame:48-60 months
Safety Issue:
Description:Survival is defined as the duration of time from date of study entry to time of death or the date of last contact. The outcome is to estimate the overall survival of patients with persistent or recurrent endometrial cancer, when treated with the combination of rucaparib, bevacizumab and atezolizumab.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Medical College of Wisconsin

Trial Keywords

  • recurrent endometerial cancer

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