The EndoBARR Trial (Endometrial Bevacizumab, Atezolizumab, Rucaparib)

Endometrial Cancer Clinical Trial

— EndoBARR  

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 Details — Status: Completed

Administrative data

• NCT number: NCT03694262
• Other study ID #: EndoBARR
• Status: Completed
• Phase: Phase 2
• Start date: July 19, 2019
• Est. completion date: April 5, 2023

Study information

• Verified date: August 2023
• Source: Medical College of Wisconsin
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: April 5, 2023
• Est. primary completion date: March 30, 2023
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinosarcoma
• Endometrial Cancer
• Endometrial Neoplasms
• Mixed Tumor, Mullerian
• Uterine Carcinosarcoma

Intervention

Drug:
• Rucaparib
Rucaparib 600mg orally twice daily by continuous dosing
• Bevacizumab
15mg/kg IV on day 1 of every cycle
• Atezolizumab
1,200mg IV on day 1 of every cycle

Locations

Country	Name	City	State
United States	St. Luke's Hospital and Health Network	Bethlehem	Pennsylvania
United States	Froedtert Lutheran Memorial Hospital	Milwaukee	Wisconsin
United States	Mount Sinai	New York	New York

Sponsors (3)

Lead Sponsor	Collaborator
Medical College of Wisconsin	Clovis Oncology, Inc., Genentech, Inc.

Country where clinical trial is conducted

United States, 

References & Publications (38)

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* Note: There are 38 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Microsatellite instability (MSI) - both genetic and epigenetic	Measurement of tumor MicroSatellite Instablility (MSI) via both qtPCR (quantitative polymerase chain reaction) and IHC (immunohistochemistry).	48-60 months
Other	Homologus recombination deficiency gene alterations	Tumor samples will assess for the genes that lead to homologus recombination deficiency.	48-60 months
Other	PD-L1 expression in the tumor	Tumor samples (from initial diagnosis) will have PD-L1 assessed by IHC (immunohistochemistry).	48-60 months
Other	Tumor mutational burden	This level will be assessed in primary patient specimens using formalin fixed, paraffin-embedded samples.	48-60 months
Other	Loss of Heterozygosity	Tumor sample will be assessed for loss of heterozygosity	48-60 months
Other	Circulating tumor DNA	Peripheral blood draw will be assessed for circulating tumor DNA	48-60 months
Other	Stool Microbiome	Samples collected prior to therapy, after the third cycle, and after conclusion will allow longitudinal assessments of variations of the microbiome from patient to patient, and changes within a single patient.	48-60 months
Other	Cardiac toxicity	Measure for cardiac strain and assess the ability of this technique to predict development of toxicity for subjects under treatment via echocardiogram derived measurements. The average strain per segment will be determined and reported on a polar map, using a 17-segment model. The global longitudinal strain (GLS) will be reported as the average strain of all 17 segments. A GLS of < -18% will be reported to be abnormal.	48-60 months
Primary	Overall Response Rate	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.	30-36 months
Secondary	Progression Free Survival	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.	48-60 months
Secondary	Number of participants with treatment-related adverse events as assessed by CTCAE V5.0	To determine the nature and degree of toxicity of treatment using the CTCAE v5.0 with this combination in this cohort of patients.	30-36 months
Secondary	Overall Survival	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.	48-60 months