| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced/recurrent solid tumors which have ATRi sensitizing biomarkers, |
|
| E.1.1.1 | Medical condition in easily understood language |
| To treat various cancer types that have specific genes expected to be sensitive to the study medication. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Module 1:
• To assess the safety and tolerability of RP-3500 in patients with eligible advanced solid tumors
• To define the maximum tolerated dose (MTD) of RP-3500 monotherapy, and determine a recommended phase 2 dose (RP2D) and schedule
Module 2:
• To assess anti-tumor activity of RP-3500 when administered to eligible patients at the RP2D and schedule in selected genetic backgrounds
Module 1 may be considered for analysis
Module 3:
• To assess the safety and tolerability of RP-3500 and talazoparib combination in eligible patients with advanced solid tumors
• To define the MTD of RP-3500 and talazoparib combination and determine RP2D and schedule |
|
| E.2.2 | Secondary objectives of the trial |
Module 1:
• Assess preliminary anti-tumor activity with RP-3500
• Characterize the PK profile of RP-3500
• Assess PK parameters of RP-3500 monotherapy in fasted and fed states
• Assess the relationship between PD biomarkers and PK of RP-3500 in a subset of patents to aid in schedule decisions and assess correlation with clinical outcomes
Module 2:
• Assess anti-tumor activity of RP-3500 in subsets of tumors tested in ARM 1
• Establish the preferred assay methods for defining how to select patients for ATRi sensitizing biomarkers for future studies
• Further characterize the PK profile of RP-3500
Module 3:
• Assess preliminary anti-tumor activity of RP-3500 and talazoparib combination in eligible patients
• Assess any PK interaction of RP-3500 and talazoparib combination
• Determine the PK/PD relationships of RP-3500 and talazoparib combination to confirm dose/schedule
• Determine activity of RP-3500 and talazoparib combination in patients who progressed after RP-3500 alone |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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
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 postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, confirmation with more than one FSH measurement is required.
13. Resolution of all toxicities of prior therapy or surgical procedures to baseline or Grade 1 (except for neuropathy, hypothyroidism requiring medication and alopecia which must have resolved to Grade ≤2).
14. Male patients with female partners of childbearing potential and WOCBP must follow a contraception method (oral contraceptives allowed) at least as conservative as Clinical Trial Facilitation Group (CTFG) recommendations during their participation in the study and for 4 months following last dose of study drug. Male patients must also refrain from donating sperm during their participation in the study and for 4 months following last dose of study drug.
15. Life expectancy ≥12 weeks after the start of the treatment according to the investigator’s judgment. |
|
| E.4 | Principal 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 to prolong the QT interval (Appendix 4) .
14. History of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) diagnosis
15. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol.
16. Patients who are receiving strong CYP3A inhibitors or inducers, P-glycoprotein (P-gP) inhibitors and/or breast cancer resistant protein (BCRP) inhibitors within 14 days prior to first dose of study drug
17. Patients who are pregnant or breastfeeding
Additional Exclusion Criteria for Module 3:
18. Known hypersensitivity to any of the ingredients of talazoparib.
19. For patients entering into Module 3b, the following additional exclusion criteria apply:
a. Rapid disease progression or threat to vital organs or critical anatomical sites (eg, CNS metastasis, respiratory failure due to tumor compression, spinal cord compression) requiring urgent alternative medical intervention
b. Significant, unacceptable or irreversible toxicities related to the study treatment
c. Other treatment discontinuation criteria are met |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety:
• Dose-limiting toxicities (DLTs)
• Incidence of Treatment-emergent adverse event (TEAEs), treatment related TEAE, TEAEs leading to death, SAE, treatment related serious adverse event (SAE), TEAE leading to study drug discontinuation, TEAE leading to dose modifications and TEAE leading to study discontinuation summarized by system organ class (SOC) and MedDRA preferred term.
• Changes in clinical laboratory parameters (hematology, chemistry, urinalysis), Common Terminology Criteria for Adverse Events (CTCAE) graded laboratory toxicities, vital signs, Eastern Cooperative Oncology Group (ECOG) performance status, ECG parameters, Physical examinations (PEs) and usage of concomitant medications
• 4β-hydroxycholesterol, a biomarker of CYP3A induction, will be evaluated at the RP2D
Efficacy:
• Objective response rate (ORR): confirmed best overall response of complete response (CR) or partial response (PR), based on investigator’s assessment using RECIST v1.1
• Duration of response (DOR), based on investigator’s assessment using RECIST v1.1
• Clinical benefit rate (CR + PR + stable disease [SD] ≥4 months), based on investigator’s assessment using RECIST v1.1
• Progression-free survival time (PFS) and rate of PFS at 6 months, based on investigator’s assessment using RECIST v1.1
• Rate of overall survival (OS) at 12 months |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety:
Throughout the Trial
Efficacy:
Confirmed overall response rate (ORR), duration of response (DOR), clinical benefit rate (CR + PR + stable disease [SD] ≥4 months), progression free survival (PFS) at 6 months, and overall survival (OS) at 12 months in the analysis population |
|
| E.5.2 | Secondary end point(s) |
Pharmacokinetics:
Blood samples will be drawn to determine RP-3500 and talazoparib PK parameters. Blood samples will be collected at the timepoints outlined in each module. Blood samples for the analysis of 4β-hydroxycholesterol, a biomarker of CYP3A induction, will be collected in patients in Module 1c at or near the RP2D (n = 10).
Biomarkers:
Pre- and on-treatment tumor biopsy samples will be collected to confirm target engagement at each dose/schedule and RP2D through measuring biomarkers such as pKAP1 and p-gammaH2Ax in pre- and on-treatment samples. Changes in the tumor-immune microenvironment also will be measured. Blood samples will be collected for ctDNA genomic analyses at timepoints outlined in each module. Baseline genomic profiles will be correlated with response to RP-3500 (or RP-3500 in combination with talazoparib).
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| PK and biomarker analysis timepoints vary by module. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Food effect and QTc evaluation |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 1 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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