This study will test the safety of the study drug, repotrectinib, in combination with chemotherapy (irinotecan and temozolomide) in children and young adults who have advanced or metastatic solid tumors. We researchers will try to find the highest dose of the study drug that causes few or mild side effects in study participants. When the researchers find this dose, we will evaluate it in a different group of participants to find out whether repotrectinib in combination with chemotherapy is an effective treatment for children and young adults who have advanced/metastatic solid tumors. Another purpose of the study is to look at the way the body absorbs, distributes, and gets rid of repotrectinib.
Myelosuppressive chemotherapy: Last dose was given at least 21 days before the start date for protocol therapy.
Biologic (anti-neoplastic agent including retinoids): Last dose given at least 7 days prior to the start date for protocol therapy.
Monoclonal antibodies: Last dose of any monoclonal antibodies must have received at least 7 days or 3 half-lives, whichever is longer, prior to the start date for protocol therapy.
Other immunotherapy (ex: tumor vaccine): Patient is eligible after 42 days of completion. Steroids are excluded from inclusion in immunotherapy.
Phase 1- patients with known bone marrow disease
Concurrent participation in another therapeutic clinical trial
Major surgery within 14 days (2 weeks) prior to C1D1. Central venous access (Broviac, MediPort) placement does not meet criteria for major surgery.
Pregnancy or lactation
Sequential
Repotrectinib
DrugTPX-0005 (Repotrectinib) will be taken orally twice daily in 28-day cycles without regard to food and will be administered orally before administration of irinotecan and temozolomide (exception: C1, TPX-0005 (Repotrectinib) will be administered once daily x 14 days, then twice daily D15-D28).
Irinotecan and temozolomide
DrugIrinotecan and temozolomide will be given as per institutional standard.
incidence of Dose Limiting Toxicity (DLTs) (phase I)
DLTs will be defined as any of the following events that are possibly, probably or definitely attributable to TPX-0005 (Repotrectinib) given in combination with chemotherapy and occurring. Grading will be evaluated according to National Cancer Institute CTCAE v5.0.
Maximum tolerated dose (MTD) (phase I)
MTD will be defined for TPX-0005 (Repotrectinib) in combination with chemotherapy. The MTD is the highest dose level of TPX-0005 (Repotrectinib) expected to cause a DLT in not more than 1/6 treated subjects. The dose escalation will follow a standard rolling 6 design (an algorithm-based extension of a standard 3+3 design).
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