Phase 1 Trial of the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Clinical Activity of RP-1664 in Participants with Advanced Solid Tumors

Prior treatment

• Other anticancer therapy while the participant is receiving trial intervention.
• Previously prescribed receptor activator of nuclear factor kappa B ligand (RANKL) inhibitor initiated less than 4 months prior to trial entry. Bisphosphonates are allowed if initiated/administered at least 28 days prior to enrollment.
• I-131 Meta-Iodo-Benzyl-Guanidine (MIGB) therapy within 6 weeks prior to initiation of trial treatment.
• Prior treatment with a PLK4 inhibitor.
• Use of radiotherapy (except for palliative reasons) within 14 days prior to trial treatment initiation.
• Participants who are receiving strong P-glycoprotein (P-gp) inhibitors and/or breast cancer resistance protein (BCRP) inhibitors within 14 days prior to first dose of trial intervention.
• Major surgical procedures ≤ 28 days prior to trial treatment initiation.
• Gastrointestinal abnormalities, including inability to take whole, intact oral medication.
• Chemotherapy, small molecule or biologic antineoplastic agent given within 21 days or < 5 half‑lives.
• Clinically significant vascular (both arterial and venous) and non‑vascular cardiac conditions, active or within 6 months prior to enrollment.

Other illness

• Moderate or severe hepatic impairment (i.e., Child-Pugh class B or C).
• Uncontrolled hypertension.
• Persistent Grade > 1 non-hematological toxicity from prior cancer therapy. Grade 2 peripheral neuropathy after documented treatment with taxanes and/or platinum-based therapy is allowed.
• Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol.
• Life-threatening illness, medical condition, active uncontrolled infection, or organ system dysfunction, or other reasons which, in the Investigator’s opinion, could compromise the participant’s safety, or interfere with or compromise the integrity of the trial outcomes.
• 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.

Lab values

• History or current condition (such as transfusion-dependent anemia, thrombocytopenia) or laboratory abnormality that might pose a significant risk to participant safety, confound the trial results, or interfere with participation for the full duration of the trial treatment.
• Current treatment with medications that are known to prolong the QT interval.
• QT interval meeting protocol-specified criteria.

Age

• Presence of other known second malignancy with the exception of any cancer that has been in complete remission for ≥ 2 years or completely resected squamous and basal cell carcinomas of the skin.

Other

• Participants who are breastfeeding at screening or planning to become pregnant (self or partner) at any time during trial participation.
• Uncontrolled, symptomatic brain metastases.

• Written informed consent or assent, according to local guidelines, signed and dated by the participant or legal guardian prior to the performance of any trial-specific procedures, sampling, or analyses. Participants with impaired decision-making capacity must have a close caregiver or legally authorized representative (LAR) present.
• Acceptable organ function at Screening.
• Acceptable hematologic function at Screening.
• Negative pregnancy test (serum) for women of childbearing potential (WOCBP) at Screening.
• Male participants with female partners of childbearing potential must follow a contraception method.
• For participants in the food effect portion of the trial, ability to consume a high-fat meal and fast for 12 hours.
• Male or female participants ≥ 18 years of age at the time of signing the informed consent.
• Ability to swallow and retain whole, intact oral medications.
• Life expectancy ≥ 4 months after the start of the treatment according to the Investigator’s judgment.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 or Lansky performance status ≥ 60%.
• Participant must have locally advanced or metastatic solid tumor that has progressed or was nonresponsive or intolerant to available therapies and for which no standard or available curative therapy exists.
• Measurable disease per RECIST v1.1 or INRC.
• Provision of archival tumor tissue (if adequate archival tumor tissue is not available, tumor tissue should be acquired by a fresh biopsy prior to enrollment).
• All participants’ tumors must have evidence from a Clinical Laboratory Improvement Amendments (CLIA)‑certified or equivalent (ex-United States [US]) laboratory: Gain or amplification of TRIM37.