MYTHIC Eligibility 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, analyses. Patients with IDMC must have a close caregiver or LAR present.
2. Male or female > 12 years of age at the time of signature of the ICF.
- Patients 12-17 years of age will be enrolled only after at least 4 patients > 18 years of age have completed at least 1 cycle of therapy.
3. Lansky performance status > 50% for patients < 16 years of age, or ECOG score of 0/1/2 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 are eligible if the patient is not a candidate for, or would be unlikely to tolerate or derive significant clinical benefit from, appropriate SOC therapy, or if the patient declines SOC therapy. Documented counseling by the center investigator on benefits/risks of SOC therapy is required for enrolled patients who decline SOC 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 lab and centrally confirmed by PODS:
- CCNE1 amplification (non-equivocal) as determined by tumor NGS or FISH
- FBXW7 deleterious mutations (eg hotspot, truncating, splice site, frameshift) identified by either a tumor or plasma NGS test
- PPP2R1A deleterious mutations (eg hotspot, truncating, splice site, frameshift) identified by either a tumor or plasma NGS test
8. The following types of endometrial cancer are eligible:
- Serous endometrial (p53 IHC must be confirmed to be abberant, aberrant p53 expression is consistent with mutant Tp53)
- Carcinosarcoma of the endometrium
- Grade 3 endometrioid and undifferentiated carcinoma (p53 IHC must be confirmed to be abberant, aberrant p53 expression is consistent with mutant Tp53; 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 following laboratory data:
13. Acceptable hematologic function at screening:
14. Negative serum pregnancy test for WOCBP at screening
- 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 participation and for 60 days after the last dose of study drug.
- Women are considered post-menopausal and not of CBP if they have had no menses for 12 months without an alternative medical cause or permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.
15. Male patients with female partners of CBP must follow a contraception method at least as conservative as CTFG recommendations during their participation in the study for 4 months following last dose. Male patients must also refrain from donating sperm during their participation and for 4 months following last dose.
16. Resolution to all toxicities of prior therapy or surgical procedures to baseline or Grade 1 (except 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 investigator's judgement.
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.
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 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 LHRH GnRH or previously prescribed RANKL inhibitor are allowed if these medications were prescribed at least 4 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 lab abnormality that might confound the study results, or interfere with the patient's participation for the full administration of the study treatment.
3. Patients who are pregnant or breastfeeding.
4. Known sensitivity to any of the ingredients of the RP-6306.
5. Patients who are unable to swallow oral medications.
6. Life-threatening illness, medical condition, active uncontrolled infection, organ system disfunction (such as ascites, coagulopathy, 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 the first dose of RP-6306.
8. Uncontrolled, symptomatic brain mets. Patients with previously treated brain mets may participate provided the mets are stable (without evidence of progression by imaging for at least 4 weeks prior to first dose and any neurologic symptoms are controlled and stable), and have no evidence of new or enlarged brain mets, and are clinically stable and off steroids for at least 7 days prior to study drug.
9. Uncontrolled hypertension (systolic BP >160 mmHg; diastolic BP >100 mmHg) despite adequate treatment prior to first dose of RP-6305.
10. Active, uncontrolled bacterial, fungal, or viral infection, including HBV, HCV, HIV, or 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+ 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 of AIDS defining conditions and status of HIV treatment.
11. Moderate or severe hepatic impairment.
12. Any of the following cardiac diseases currently or within the last 6 months as defined by NYHA >Class 2:
- Unstable angina pectoris
- Congestive heart failure
- Acute myocrdial infarction
- Conduction abnormality not controlled with pacemake or medication
- Significant ventricular or supraventricular arrhythmias (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible)
- Clinically significant electrolyte abnormalities (eg hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden, unexplained death or long ECG interval measured from the onset of QRS complex to the end of the T wave syndrome
13. Mean resting QT interval corrected QT interval (Qtc) using the Fridericia formula >450 msec/male and >470 msec/female (as calculated per institutional standards) obtained fro m3 ECGs 2-5 minutes apart at study entry.
14. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and / or follow-up procedures outlined in the protocol.
15. Current treatment with medications that are well-known to prolong the QT interval.
16. Patients who are receiving strong CYP3A inhibitors or inducers within 14 days prior to first dose of study drug.