| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced solid tumors with CCNE1 amplification or deleterious mutations in FBXW7 or other proprietary gene |
|
| E.1.1.1 | Medical condition in easily understood language |
| To treat various cancer types that have specific mutations 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 | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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:
• Assess the safety and tolerability of RP-6306 in patients with eligible advanced solid tumors
• Define the maximum tolerated dose (MTD) of RP- 6306 monotherapy, and determine a recommended Phase 2 dose (RP2D) and preferred schedule
Module 2:
• Assess the safety and tolerability of RP-6306 in combination with RP-3500 in patients with molecularly selected, advanced solid tumors
• Define the maximum tolerated dose (MTD) of RP-6306 in combination with RP-3500, and determine a recommended Phase 2 dose (RP2D) and preferred schedule
|
|
| E.2.2 | Secondary objectives of the trial |
Module 1:
• Assess pharmacokinetic (PK) parameters of RP- 6306 monotherapy in fasted and fed states
• Assess the relationship between pharmacodynamic biomarkers and PK of RP-6306 at different dose levels and/or schedules
• Assess preliminary anti-tumor activity achieved with RP-6306 monotherapy in patients with each of the molecular subsets of advanced solid tumors: harboring either CCNE1 amplification or deleterious mutations in F-box and WD repeat domain containing 7 (FBXW7) or other proprietary gene
Module 2:
• Assess pharmacokinetic (PK) parameters of RP-6306 and RP-3500 when dosed in combination
• Assess preliminary anti-tumor activity achieved with RP-6306 in combination with RP-3500 in patients with advanced solid tumors harboring CCNE1 amplification, FBXW7 or proprietary gene deleterious mutations, or other genomic alterations with mechanistic rationale as agreed upon by the Sponsor and Investigator |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent and assent, according to local guidelines, signed and dated by the participating patient or legal guardian prior to the performance of any study-specific procedures, sampling, or analyses.
2. Male or female and ≥12 years-of-age at the time of signature of the informed consent form (ICF).
3. Lansky performance status ≥50 for patients ≤16 years of age, or ECOG score of 0, 1, or 2 (Module 2 ECOG 0 or 1) for patients >16 years of age.
4. All patients must have locally advanced or metastatic resistant or refractory solid tumors. Patients <18 years-of-age will be eligible only if standard or available curative therapy does not exist. Patients ≥18 years-of-age are eligible if, in the opinion of the investigator, the patient is not a candidate for, or would be unlikely to tolerate or derive significant clinical benefit from, appropriate standard-of-care therapy, or if the patient declines standard-of-care therapy.
5. Patients <18 years of age must weigh at least 40 kg.
6. Archived tumor tissue sample available or lesion that can be safely biopsied if the archival sample is not available.
7. All patient’s tumors, except for types of endometrial cancer listed in criteria #8, must have evidence of at least one of the following as reported by a local CLIA-certified or equivalent (ex-United States [US]) laboratory and centrally confirmed by PODS:
a. CCNE1 amplification (non-equivocal) as determined by either a tumor or plasma NGS test, or FISH
b. FBXW7 deleterious mutations identified by either a tumor or plasma NGS test
c. Proprietary gene deleterious mutations identified by either a tumor or plasma NGS test
d. For backfill cohorts, tumors with other genes with mechanistic rationale agreed upon between the Sponsor and Investigator will be accepted.
8. The following types of endometrial cancer are eligible (for Module 1 only):
a. Serous endometrial cancer (p53 IHC must be confirmed to be aberrant or local NGS report confirming TP53 loss of function mutation must be provided)
b. Carcinosarcoma of the endometrium
c. Grade 3 endometrioid and undifferentiated carcinoma (p53 IHC must be confirmed to be aberrant or local NGS report confirming TP53 loss of function mutation must be provided; MMR IHC must be retained and/or tumor must be MSS; polymerase epsilon (POLE) hypermutated type must be excluded)
9. Measurable disease as per RECIST v1.1.
10. Ability to comply with the protocol and study procedures detailed in the Schedule of Assessments.
11. Ability to swallow and retain oral medications.
12. Acceptable organ function at Screening, as evidenced by the following laboratory data:
a. Serum creatinine ≤1.5 × 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) ≤3.0 × ULN
13. Acceptable hematologic function at Screening:
a. No red blood cell (RBC) or platelet transfusions or growth factors within 7 days of the first dose of RP-6306
b. Hemoglobin ≥9.0 g/dL (or ≥10.0 g/dL for Module 2 only)
c. ANC ≥1500 cells/mm3
d. Platelet count ≥100,000 cells/mm3
14. Negative pregnancy test (serum) for women of childbearing potential at Screening.
15. Male patients with female partners of childbearing potential must follow a contraception method (oral contraceptives allowed) during their participation in the study for 6 months following last dose of drug. Male patients must also refrain from donating sperm during their participation in the study and for 6 months following last dose of study drug.
16. 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).
17. Any prior radiation must have been completed at least 7 days prior to the start of study drugs, and patients must have recovered from any acute adverse effects prior to the start of study treatment.
18. Life expectancy ≥12 weeks after the start of the treatment according to the investigator’s judgment.
Additional Inclusion Criteria for Module 1c:
19. Ability to consume a high-fat meal and fast for 12 hours. Module 1c will only be open to patients ≥18 years-of-age. |
|
| E.4 | Principal exclusion criteria |
1. Chemotherapy or small molecule antineoplastic agent given within 21 days or <5 half-lives, whichever is shorter, prior to first dose of study drug. For drugs for which 5 half-lives is ≤21 days, a minimum of 10 days between termination of the prior treatment and administration of RP-6306 treatment is required. For patients with breast or prostate cancer, continuation of long-term luteinizing hormone-releasing hormone (LHRH), gonadotrophin releasing hormone (GnRH), or previously prescribed Receptor Activator of Nuclear Factor kB Ligand (RANKL) inhibitor are allowed if these medications were prescribed for at least 3 months before trial entry. Bisphosphonates are allowed if prescribed at least 28 days prior to enrollment.
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. Patients who are pregnant or breastfeeding.
4. Known sensitivity to any of the ingredients of RP-6306 (and RP-3500 for Module 2).
5. Patient who are unable to swallow oral medications.
6. Life-threatening illness, medical condition, active uncontrolled infection, or organ system dysfunction (such as ascites requiring drainage within 4 weeks prior to enrollment, coagulopathy, or encephalopathy), or other reasons which, in the investigator’s opinion, could compromise the participating patient’s safety, or interfere with or
compromise the integrity of the study outcomes.
7. Major surgery (excluding placement of vascular access) within 4 weeks prior to first dose of RP-6306.
8. 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 enlarged brain metastases, and are clinically stable and off steroids for at least 7 days prior to study drug.
9. Uncontrolled hypertension (systolic blood pressure [BP] ≥160 mmHg; diastolic BP ≥100 mmHg) despite adequate treatment prior to first dose of RP-6306 (and RP-3500 for Module 2).
10. 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 AIDSrelated outcomes could be considered eligible. Eligibility criteria for HIV positive patients should be evaluated and discussed with the sponsor’s medical monitor and will be based on current and past CD4 and T-cell counts, history (if any) of AIDS defining conditions (e.g., opportunistic infections), and status of HIV treatment
11. Moderate or severe hepatic impairment (i.e., Child-Pugh class B or C).
12. Any of the following cardiac diseases currently or within the last 6 months as defined by New York Heart Association (NYHA) ≥Class 2:
a. Unstable angina pectoris
b. Congestive heart failure
c. Acute myocardial infarction
d. Conduction abnormality not controlled with pacemaker or medication
e. Significant ventricular or supraventricular arrhythmias (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible)
f. Clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or long ECG interval measured from the onset of the QRS complex to the end of the T wave (QT) syndrome
13. Mean resting QT interval corrected for heart rate (QTc) interval using the Fridericia formula (QTcF) >450 msec/male and >470 msec/female (as calculated per institutional standards) obtained from 3 ECGs >1 minute apart at study entry.
14. Current treatment with medications that are well-known to prolong the QT interval.
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 (and P-gp inhibitors and/or BCRP inhibitors for Module 2 only) within 14 days prior to first dose of study drug.
Additional exclusion criteria for Module 2:
17. Prior therapy with an ATR, DNA-PK, PKMYT1, or WEE1 inhibitor. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Treatment-emergent adverse events (TEAEs), physical examinations (PEs), safety laboratory assessments, electrocardiograms (ECGs), and vital sign measurements
• Dose-limiting toxicities (DLTs)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Module 1:
• Plasma concentrations of RP-6306) with calculation of maximum observed plasma concentration (Cmax), time to maximum observed plasma concentration (Tmax), minimum observed plasma concentration (Cmin), area under the plasma concentration-time curve (AUC), elimination t1/2, and other parameters as appropriate.
• Assessment of biomarkers (e.g., g-H2AX, p-CDK1 Thr14) in pre- and on-treatment biopsies, and circulating tumor DNA (ctDNA) dynamics during treatment.
• Best percent change in tumor size from baseline, objective response rate (ORR), tumor marker response, duration of response (DOR), clinical benefit rate (CBR), available progression-free survival (PFS), and overall survival (OS) data
Module 2:
• Plasma concentrations of RP-6306 and RP-3500 with calculation of maximum observed plasma concentration (Cmax), time to maximum observed plasma concentration (Tmax), minimum observed plasma concentration (Cmin), area under the plasma concentration-time curve (AUC), elimination t1/2, and other parameters as appropriate.
• Best percent change in tumor size from baseline, ORR, DOR, CBR, tumor marker response; PFS, and OS data
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 |
| Tolerability (for all modules) and food effect (for Module 1) |
|
| 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) | No |
| 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 | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| 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 States |
| Denmark |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 30 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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