A phase 1/2a trial to study how safe and tolerable RP-3500 is when administered along or in combination with talazoparib in patients with certain types of cancer

Phase 1

• Conditions: Advanced/recurrent solid tumors which have ATRi sensitizing biomarkers, including:- ATM loss- RNase H2 loss- Loss of other ATRi sensitizing biomarkers (HyBAR: Hypotheses Beyond ATM and RNase H2) HyBAR genes are defined as the following: ATRIP, BRCA1, BRCA2, CDK12, CHTF8, FZR1, MRE11, NBN, PALB2, RAD17, RAD50, RAD51B, REV3L, SETD2 or other genes decided upon between the sponsor and investigators; MedDRA version: 21.1Level: LLTClassification code 10065252Term: Solid tumorSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2020-000301-87-GB
• Lead Sponsor: Repare Therapeutics

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2020-08-03
• Last Update Posted: 5 January 2021

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 239

Inclusion Criteria

1. Written informed consent, according to local guidelines, signed and dated by the patient or legal guardian prior to the performance of any study-specific procedures, sampling, or analyses.
2. Male or female and =18 years-of-age at the time of signature of the ICF.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.
4. Histologically confirmed solid tumors resistant or refractory to standard treatment and/or patients who are intolerant to standard therapy.
5. Measurable disease as per RECIST v1.1
6. Existing biomarker profile (tumor tissue or plasma) reported from a local test obtained in a CAP/CLIA, ISO or equivalent lab per institutional guidelines:
a. Documented and confirmed by central review of local NGS reports by PODS, deleterious genomic alterations for at least 1 of the following genes: ATM, ATRIP, BRCA1, BRCA2, CDK12, CHTF8, FZR1, MRE11, NBN, PALB2, RAD17, RAD50, RAD51B, REV3L, RNAseH2A, RNAseH2B, SETD2 or other genes decided upon between the sponsor and investigators.
b. Or documented complete loss of ATM or RNase H2 protein expression by IHC.
7. Provision of tumor tissue at Screening as per laboratory manual specifications. If archival tissue is available, the date of tumor tissue acquisition (e.g. biopsy or surgical resection) must be no older than 12 months from tissue procurement to enrollment. Enrolling centers must either provide 15 unstained slides, a tissue block with a minimum of 30% tumor content or obtain an adequate fresh biopsy sample prior to treatment. If adequate archived tumor tissue is not available and/or a fresh biopsy cannot be safely performed, the patient may still be eligible with prior sponsor approval.
8. Ability to comply with the protocol and study procedures detailed in the Schedule of Assessments.
9. Ability to swallow and retain oral medications.
10. Acceptable organ function at Screening, as evidenced by the following laboratory data:
a. Serum creatinine =1.5 × upper limit of normal (ULN) or calculated creatinine clearance =60 mL/min using the Cockcroft-Gault equation or by 24-hour urine collection
b. Total bilirubin =1.5 × ULN or <3.0 × ULN if known Gilbert’s disease.
c. Serum albumin =2.5 g/dL
d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =2.5 × ULN unless liver metastases are present and thought to be a reason for AST/ALT elevation, in which case they must be =5 × ULN
11. Acceptable hematologic function at Screening
a. No red blood cell or platelet transfusions or growth factors within 7 days of the first dose of RP-3500
b. Hemoglobin =9.5 g/dL
c. ANC =1700 cells/mm3
d. Platelet count =150,000 cells/mm3
12. Negative pregnancy test (serum) for women of childbearing potential (WOCBP) at Screening.
a. WOCBP is defined as fertile, following menarche and until becoming post-menopausal unless permanently sterile. WOCBP, who are sexually active, and their partners must agree to use a highly effective form of contraception as detailed in Appendix 1 throughout their participation during study treatment and for 7 month after the last dose of study drug(s).
b. Women are considered post-menopausal and not of childbearing potential if they have had no menses for 12 months without an alternative medical cause or permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a po

Exclusion Criteria

1. Chemotherapy, small molecule anticancer or biologic anticancer therapy given within 14 days prior to first dose of study drug. For patients with breast or prostate cancer continuation of long-term luteinizing hormone-releasing hormone (LHRH) or previously prescribed Receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor or bisphosphonates is allowed.
2. History or current condition (such as transfusion dependent anemia or thrombocytopenia), therapy, or laboratory abnormality that might confound the study results, or interfere with the patient’s participation for the full duration of the study treatment.
3. Prior therapy with an ATR or DNA-dependent protein kinase (DNA-PK) inhibitor.
4. Known hypersensitivity to any of the ingredients of RP-3500.
5. Life-threatening illness, medical condition, active uncontrolled infection, or organ system dysfunction (such as coagulopathy, encephalopathy or ascites requiring drainage within 4 weeks prior to enrollment) or other reasons which, in the investigator’s opinion, could compromise the patient’s safety, or interfere with or compromise the integrity of the study outcomes.
6. Uncontrolled, symptomatic brain metastases. Patients with previously treated brain metastases may participate provided the metastases are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of study drug and any neurologic symptoms are controlled and stable), have no evidence of new or enlarging brain metastases, and are clinically stable off steroids for at least 7 days prior to study drug.
7. Uncontrolled hypertension (systolic blood pressure [BP] =160 mmHg; diastolic BP =100 mmHg) despite adequate treatment prior to first dose of RP-3500.
8. Patients with active, uncontrolled bacterial, fungal, or viral infection, including hepatitis B virus (HBV), hepatitis C virus (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness. In equivocal cases, patients whose viral load is negative, may be eligible. HIV seropositive patients who are healthy and low risk for AIDS related outcomes could be considered eligible. Eligibility criteria for HIV positive patients should be evaluated and discussed with sponsor’s Medical Monitor, and will be based on current and past CD4 and T-cell counts, history (if any) of AIDS-defining conditions (eg, opportunistic infections), and status of HIV treatment.
9. Moderate or severe hepatic impairment (ie, Child-Pugh class B or C).
10. History or presence of an abnormal ECG that is clinically significant in the investigator’s opinion, including complete left bundle branch block, second- or third-degree heart block, or recent history of myocardial infarction that in the opinion of the investigator will pose an increased risk of rhythm abnormalities.
11. QT interval corrected using Fridericia’s formula (QTcF) >470 msec demonstrated by at least 2 ECGs >30 minutes apart.
12. History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease (eg, severe left ventricular systolic dysfunction, left ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (eg, hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or long QT syndrome
13. Current treatment with medications that are well-known

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified