MAGNETIC Eligibility Criteria

Inclusion Criteria

1. Written informed consent, according to local guidelines, signed and dated by the participating patient prior to the performance of any study-specific procedures, sampling, or analyses. Patients with impaired decision-making capacity must have a close caregiver or legally authorized representative (LAR) present.
2. Males or females ≥18 years old at the time of signature of the ICF.
3. ECOG performance status of 0 or 1.
4. All patients must have locally advanced or metastatic resistant or refractory solid tumors. Patients will be eligible only if standard or available curative therapy does not exist.
5. A recent archival tumor tissue sample must be shipped to the Sponsor’s central laboratory. Patients who do not have archival tumor tissue that meets the specifications detailed in the Laboratory Manual should undergo a fresh tumor biopsy prior to treatment if it is considered safe to perform. 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.
6. All patient’s tumors must have evidence of at least one of the following as reported by a local CLIA-certified or equivalent (ex-United States [US]) laboratory:
                     a. CCNE1 amplification (non-equivocal) as determined by tumor NGS or FISH
                     b. FBXW7 and/or PPP2R1A deleterious mutations (eg, hotspot, truncating, splice site, or frameshift) identified by either                              tumor or plasma NGS test
                      Note: For all patients, an anonymized/redacted Molecular Pathology or other report(s) describing CCNE1, FBXW7, or                                    PPP2R1A genomic alterations should be submitted to the Sponsor or designee during Screening to confirm eligibility.
7. Measurable disease as per RECIST v1.1.
8. Ability to comply with the protocol and study procedures detailed in the Schedule of Assessments.
9. Acceptable organ function at Screening, as evidenced by the following laboratory data:
                       a. GFR ≥ 60 mL/min/1.73 m2 using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation or                                 calculated creatinine clearance ≥60 mL/min using Cockcroft-Gault equation (or by 24-hour urine collection)
                       b. Total bilirubin ≤1.5 × upper limit of normal (ULN) or <3.0 × ULN if known Gilbert’s disease
                       c. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 × ULN
10. Acceptable hematologic function at Screening, defined as follows:
                       a. No RBC or platelet transfusions or growth factors within 7 days of the first dose of treatment
                       b. Hemoglobin ≥9.5 g/dL
                       c. ANC ≥1500 cells/μL
                       d. Platelet count ≥100 000 cells/μL
11. Negative pregnancy test (serum) for women of childbearing potential (WOCBP) at Screening.                                                                                       a. WOCBP is defined as fertile, following menarche and until becoming postmenopausal, 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 the study and for 6 months after the last dose of study                                 treatment.
                    b. Women are considered postmenopausal and not of childbearing potential if they have had no menses for 12 months                                    without an alternative medical cause or permanent sterilization methods including 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 1 FSH                                      measurement is required.
12. Male patients with female partners of childbearing potential must follow a contraception method (oral contraceptives allowed) at least as conservative as Clinical Trial Facilitation Group recommendations during their study participation and for 3 months after last dose of study treatment. Male patients must also refrain from donating sperm during their participation in the study and for 3 months after last dose of study treatment.
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. Any prior radiation must have been completed at least 7 days prior to the start of study treatment, and patients must have recovered from any acute adverse effects prior to the start of study treatment.
15. Life expectancy ≥12 weeks after the start of the treatment according to the Investigator’s judgment.

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 treatment. 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 and gemcitabine treatment is required.
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 or gemcitabine.
5. Patients who are unable to swallow oral medications.
6. Prior treatment with a Wee1-like protein kinase (WEE1) inhibitor or PKMYT1 inhibitor.                                                                          7. Life-threatening illness, medical condition, active uncontrolled infection, or organ system dysfunction (such as ascites, 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.
8. Major surgery within 4 weeks prior to first dose of study treatment.
9. Uncontrolled, symptomatic brain metastases. Patients with previously treated brain metastases may participate provided the metastases are stable (without evidence of progression by imaging within 4 weeks prior to the first dose of study treatment and any neurologic symptoms are controlled and stable), they have no evidence of new or enlarged brain metastases, and they are clinically stable and off steroids for at least 7 days prior to study treatment.
10. Uncontrolled hypertension (systolic blood pressure [BP] ≥160 mmHg and diastolic BP ≥100 mmHg) despite adequate treatment prior to first dose of study treatment.
11. Active, uncontrolled bacterial, fungal, or viral infection, including hepatitis B virus, 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 the 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.
12. Moderate or severe hepatic impairment (ie, Child-Pugh Class B or C).
13. 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 relevant electrolyte abnormalities (eg, 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
14. 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 taken ≥1 minute apart at study entry.
15. Current treatment with medications that are well known to prolong the QT interval.                                                                            16. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol.
17. Patients who are receiving strong cytochrome P450 (CYP) 3A inhibitors or inducers within 14 days prior to first dose of study treatment