A Study of RP-3500 in Combination With Standard Radiation Therapy in People With Solid Tumor Cancer

Inclusion Criteria:

• Histologically confirmed malignancy with at least one metastatic lesion amenable toradiotherapy. Bone, visceral, and soft tissue are eligible.

• Mutation in ATM (deleterious or VUS; somatic or germline; monoallelic or biallelic)

• Note: Homozygous Deletion in the ATM gene will also be allowed

• ECOG performance status 0-2

• Age ≥18 years

• Expected survival greater than 6 months

• Participant or Legally Authorized Representative (LAR) able to provide writteninformed consent

• Patients of reproductive potential must agree to practice an effective contraceptivemethod

• Ability to swallow capsules and retain oral medications

• Acceptable organ function at Screening, as evidenced by the following laboratorydata:

1. Serum creatinine ≤1.5 × upper limit of normal (ULN) or calculated creatinineclearance ≥60 mL/min using the Cockcroft-Gault equation or by 24-hour urinecollection

2. Total bilirubin ≤1.5 × ULN or <3.0 × ULN if known Gilbert's disease

3. Serum albumin ≥2.5 g/dL

4. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULNunless liver metastases are present and thought to be a reason for AST/ALTelevation, in which case they must be ≤5 × ULN

• Acceptable hematologic function at Screening:

1. No red blood cell or platelet transfusions or growth factors within 7 days ofthe first dose of RP-3500

2. Hemoglobin ≥9.5 g/dL

3. ANC ≥1700 cells/mm^3

4. Platelet count ≥130,000 cells/mm^3

• Resolution of all toxicities of prior therapy or surgical procedures to baseline orGrade 1 (except for neuropathy, hypothyroidism requiring medication and alopecia canbe resolved to Grade ≤2)

• Negative pregnancy test (serum or urine) for women of childbearing potential (WOCBP)at Screening and prior to first study drug. Non-WOCBP is defined as 1) adequate timeof amenorrhea for > 12 months plus adequate FSH level or 2) surgically oranatomically infertile

• Male patients with female partners of childbearing potential and WOCBP must follow acontraception method (oral contraceptives allowed) at least as conservative asClinical Trial Facilitation Group (CTFG) recommendations during their participationin the study. WOCBP must follow the recommendations until 6 months following lastdose of study drug and male patients must follow the recommendations for 6 monthsfollowing last dose of study drug. Male patients must also refrain from donatingsperm during their participation in the study and for 6 months following last doseof study drug

Exclusion Criteria:

• Previous radiotherapy to the intended treatment site

• Prior therapy with an ATR or DNA-dependent protein kinase (DNA-PK) inhibitor

• Serious medical co-morbidities precluding radiotherapy

• Pregnant or breast-feeding women

• No other concurrent systemic therapy during the entire duration of protocoltreatment. Patients can have other systemic treatments up until the start ofprotocol treatment. Patients can also have other systemic treatments after thecompletion of protocol treatments

• Known hypersensitivity to any of the ingredients of RP-3500

• Uncontrolled hypertension (systolic blood pressure [BP] ≥160 mmHg; diastolic BP ≥100mmHg) despite adequate treatment prior to first dose of RP-3500

• Patients with active, uncontrolled bacterial, fungal, or viral infection, includinghepatitis B virus (HBV), hepatitis C virus (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness. In equivocalcases, patients whose viral load is negative, may be eligible. HIV seropositivepatients who are healthy and low risk for AIDS related outcomes could be consideredeligible. Eligibility criteria for HIV positive patients should be evaluated anddiscussed, and will be based on current and past CD4 and T-cell counts, history (ifany) of AIDS-defining conditions (eg, opportunistic infections), and status of HIVtreatment

• Moderate or severe hepatic impairment (ie, Child-Pugh class B or C)

• History or presence of an abnormal ECG that is clinically significant in theinvestigator's opinion, including complete left bundle branch block, second- orthird-degree heart block, or recent history of myocardial infarction that in theopinion of the investigator will pose an increased risk of rhythm abnormalities

• History of ventricular dysrhythmias or risk factors for ventricular dysrhythmiassuch as structural heart disease (eg, severe left ventricular systolic dysfunction,left ventricular hypertrophy), coronary heart disease (symptomatic or with ischemiademonstrated by diagnostic testing), clinically significant electrolyteabnormalities (eg, hypokalemia, hypomagnesemia, hypocalcemia), or family history ofsudden unexplained death or long QT syndrome

• Current treatment with medications that are well-known to prolong the QT interval

• Psychological, familial, sociological, or geographical conditions that do not permitcompliance with the protocol and/or follow-up procedures outlined in the protocol

• Patients who are receiving strong CYP3A inhibitors or inducers, P-gp inhibitorsand/or BCRP inhibitors

• Patients with germline homozygous ATM mutations