PEEL-224, Vincristine and Temozolomide for the Treatment of Adolescents and Young Adults with Relapsed or Refractory Sarcomas

Inclusion Criteria

• Patients in all cohorts must have relapsed or refractory disease after standard therapy
• PHASE I: Evaluable or measurable disease; and
• PAHSE I: Histologic diagnosis of sarcoma
• PHASE II (EWS): Response Evaluation Criteria in Solid Tumors (RECIST) measurable disease at study entry
• PHASE II (EWS): Histologic diagnosis consistent with Ewing sarcoma; and
• PHASE II (EWS): Molecular evidence of a FET-ETS family translocation including but not limited to any of the following: * EWSR1::FLI1, EWSR1::ERG, EWSR1::ETV1, EWSR1::ETV4, EWSR1::FEV, FUS::FLI1, FUS::ERG
• PHASE II (DSRCT): RECIST measurable disease at study entry
• PHASE II (DSRCT): Histologic diagnosis consistent with DSRCT; and
• PHASE II (DSRCT): Molecular evidence of an EWSR1::WT1 fusion
• PHASE II (OTHER SARCOMA): RECIST evaluable or measurable disease; and
• PHASE II (OTHER SARCOMA): Histologic diagnosis of sarcoma. Patients with EWS or DSRCT with evaluable but not measurable disease may participate in this cohort
• PHASE II (OTHER SARCOMA): Slots in this cohort will include three dedicated slots for patients with rhabdomyosarcoma, three dedicated slots for patients with osteosarcoma and three dedicated slots for patients with other translocation-associated round cell sarcomas
• ≥ 12 years and ≤ 49 years
• Patients must be ≥ 40 kg
• Karnofsky ≥ 50% for patients > 16 year of age and Lansky ≥ 50% for patients ≤ 16 years of age
• Absolute neutrophil count (ANC) ≥ 1,000/uL (for subjects without bone marrow involvement by disease)
• Platelet count ≥ 100,000/uL (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) (for subjects without bone marrow involvement by disease)
• ANC ≥ 750 /uL (for subjects with bone marrow involvement by disease)
• Platelets ≥ 50,000 /uL (may receive platelet transfusions) (for subjects with bone marrow involvement by disease)
• Not known to be refractory to red cell and/or platelet transfusions (for subjects with bone marrow involvement by disease)
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70ml/min/1.73 m^2 or a serum creatinine based on age/sex as follows: * 12 to < 13 years: Maximum serum creatinine 1.2 mg/dL (male), 1.2 mg/dL (female) * 13 to < 16 years: Maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female) * >= 16 years: Maximum serum creatinine 1.7 mg/dL (male),1.4 mg/dL (female)
• Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age
• Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) ≤ 110 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L
• Fridericia's corrected QT interval (QTc) < 480 msec
• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy except organ function as noted above. Patients must meet the following minimum washout periods prior to enrollment: * Myelosuppressive chemotherapy: At least 14 days after the last dose of myelosuppressive chemotherapy * Radiotherapy: ** At least 14 days after local radiation (XRT) (small port, including cranial radiation); ** At least 90 days must have elapsed after prior total body irradiation (TBI), craniospinal XRT or if > 50% radiation of pelvis; ** At least 42 days must have elapsed if other substantial bone marrow (BM) radiation. * Small molecule biologic therapy: At least 7 days following the last dose of a biologic agent. * Monoclonal antibody: At least 21 days must have elapsed after the last dose of antibody. * Myeloid and platelet growth factors: At least 14 days following the last dose of long-acting myeloid growth factor (e.g. Neulasta) or 7 days following short-acting myeloid or platelet growth factor. * Autologous hematopoietic stem cell transplant and stem cell boost: Patients must be at least 60 days from day 0 of an autologous stem cell transplant or stem cell boost. * Cellular Therapies (e.g., chimeric antigen receptor therapy [CART], natural killer [NK]-cell based therapy): The patient must be and at least 42 days from cellular therapy administration. * Major Surgery: At least 2 weeks from prior major surgical procedure. Note: Biopsy, central nervous system (CNS) shunt placement/revision, and central line placement/removal are not considered major. * Irinotecan, liposomal irinotecan, and/or temozolomide: Patients may have received prior irinotecan, liposomal irinotecan, and/or temozolomide. ** NOTE: Patients who have had progressive disease while receiving irinotecan and temozolomide in combination will be excluded from the Phase 2 EWS and DSRCT cohorts only
• For patients with metastatic disease to the CNS enrolling to the phase 1 portion of the trial or the “other sarcoma” cohort, any baseline neurologic deficits (including seizure) must be stable for at least one week prior to study enrollment. Patients with CNS metastatic disease receiving corticosteroids must be on a stable or decreasing dose at time of study entry. Patients with CNS metastatic disease will not be eligible for the phase 2 EWS and DSRCT cohorts
• Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• The effects of PEEL-224 in combination with temozolomide and vincristine on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of PEEL-224 administration
• Ability to understand and/or the willingness of the patient (or parent or legally authorized representative, if minor) to provide informed consent, using an institutionally approved informed consent procedure
• Any participant must obtain prior approval from insurance to reimburse oral temozolomide for the duration of the study or agree to self-pay for oral temozolomide

Exclusion Criteria

• Patients who have received prior treatment with PEEL-224
• Patients who have had progressive disease while receiving irinotecan and temozolomide in combination will be excluded from the Phase 2 EWS and DSRCT cohorts only
• Participants who are receiving any other anti-cancer agents for this condition
• Patients receiving strong P450 CYP1A2 and CYP3A4 inhibitors and/or inducers with 14 days of the first planned dose of PEEL-224. * NOTE: levofloxacin is permitted and preferred over ciprofloxacin for patients needing a fluoroquinolone
• Patients who have received a solid organ or allogeneic stem cell transplant
• Pregnant participants, given that the effects of PEEL-224 on the developing human fetus are unknown
• Breastfeeding mothers, because there is an unknown risk for adverse events in nursing infants secondary to treatment of the mother with PEEL-224
• Patients with a history of allergic reactions attributed to PEGylated drugs, camptothecins, temozolomide or vincristine
• Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements