Histologically confirmed malignancy with at least one metastatic lesion amenable to radiotherapy. Bone, visceral, and soft tissue are eligible
Mutation in ATM (deleterious or VUS; somatic or germline; monoallelic or biallelic)
ECOG performance status 0-2
Age ≥18 years
Expected survival greater than 6 months
Participant or Legally Authorized Representative (LAR) able to provide written informed consent
Patients of reproductive potential must agree to practice an effective contraceptive method
Ability to swallow capsules and retain oral medications
Acceptable organ function at Screening, as evidenced by the following laboratory data
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
Total bilirubin ≤1.5 × ULN or <3.0 × ULN if known Gilbert's disease
Serum albumin ≥2.5 g/dL
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
Acceptable hematologic function at Screening
No red blood cell or platelet transfusions or growth factors within 7 days of the first dose of RP-3500
Hemoglobin ≥9.5 g/dL
ANC ≥1700 cells/mm^3
Platelet count ≥130,000 cells/mm^3
Resolution of all toxicities of prior therapy or surgical procedures to baseline or
Grade 1 (except for neuropathy, hypothyroidism requiring medication and
alopecia can be 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 time of amenorrhea for > 12 months plus adequate FSH level or 2) surgically or anatomically infertile
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. WOCBP must follow the recommendations until 7 months following last dose of study drug and male patients must follow the recommendations 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
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 protocol treatment. Patients can have other systemic treatments up until the start of protocol treatment. Patients can also have other systemic treatments after the completion of protocol treatments
Known hypersensitivity to any of the ingredients of RP-3500
Uncontrolled hypertension (systolic blood pressure [BP] ≥160 mmHg; diastolic BP ≥100 mmHg) despite adequate treatment prior to first dose of RP-3500
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, 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
Yes for 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, 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 exclusion criteria 8
No for 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, 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 exclusion criteria 8
Not sure for 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, 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 exclusion criteria 8
Moderate or severe hepatic impairment (ie, Child-Pugh class B or C)
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
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
Current treatment with medications that are well-known to prolong the QT interval
Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol
Patients who are receiving strong CYP3A inhibitors or inducers, P-gp inhibitors and/or BCRP inhibitors
Patients with germline homozygous ATM mutations