Phase 1/2 Study of Vincristine and Temozolomide in Combination With PEN-866 for Adolescents and Young Adults With Relapsed or Refractory Solid Tumors
Phase 1/2 Study of Vincristine and Temozolomide in Combination With PEN-866 for Adolescents and Young Adults With Relapsed or Refractory Solid Tumors
Background:
The drug PEN-866 can remain in tumor cells longer than it does in normal cells. It also may be more effective than other drugs at treating Ewing sarcoma and rhabdomyosarcoma. Researchers want to learn if combining PEN-866 with other drugs can treat certain cancers in adolescents and young adults.
Objective:
To learn if the combination of PEN-866 with vincristine and temozolomide can be used to treat adolescents and young adults with solid tumors that have returned after or did not respond to standard treatments, or for which there are no standard treatments.
Eligibility:
People ages 12-39 years who have solid tumors, Ewing sarcoma, or rhabdomyosarcoma that returned after or did not respond to standard treatments.
Design:
Participants will be screened with a medical history, physical exam, and eye exam. They will have heart function tests. They may have imaging scans of the chest, abdomen, and pelvis. They will give blood and urine samples. They may have a tumor biopsy. Some samples will be used for genetic testing. Some screening tests will be repeated during the study.
Participants will get 3 drugs for up to 18 cycles. Each cycle lasts 21 days. They will get PEN-866 and vincristine by IV infusion (a tube in their vein) on Days 1 and 8 of each cycle. They will take temozolomide by mouth on Days 1-5 of each cycle.
Participants will complete questionnaires about their physical, mental, and social health.
Participants will have a follow-up visit 30 days after treatment ends. They may be contacted by phone or email for the rest of their life.
Background:
Irinotecan is a prodrug of an inhibitor of topoisomerase 1 (active metabolite is SN-38) with known activity in sarcomas, however it has limitations including suboptimal bioavailability and systemic side effects including severe diarrhea and bone marrow suppression.
Preclinical and clinical evidence has demonstrated that prolonged exposure to topoisomerase 1 inhibition produces superior responses in pediatric-type sarcomas, compared to shorter exposures of irinotecan.
PEN-866 is a novel molecule consisting of SN-38 conjugated to a heat shock protein 90 (HSP90) inhibitor that has been shown to have a pharmacokinetic (PK) advantage over irinotecan in preclinical models.
Preclinical and clinical data have shown that PEN-866 acts as a tumor delivery agent for SN-38, allowing SN-38 to remain in tumor cells substantially longer than it remains in normal cells.
In preclinical models of Ewing sarcoma and rhabdomyosarcoma, PEN-866 has superior efficacy and pharmacodynamics compared to irinotecan.
PEN-866 has completed phase 1 testing in adults as a single agent but has yet to be tested in any combinations.
Vincristine/irinotecan/temozolomide (VIT) is a standard relapse regimen for several pediatric sarcomas, with objective responses reported in a subset of participants with Ewing sarcoma and rhabdomyosarcoma.
Objectives:
Phase 1: Determine the maximum tolerated/recommended phase 2 dose (MTD/RP2D) of PEN-866 that can be combined with vincristine and temozolomide in adolescent and young adult (AYA) participants (12-39 years) with relapsed or refractory solid tumors
Phase 2: Determine the objective response rate (CR + PR by RECIST v1.1) of the combination of vincristine, temozolomide and PEN-866 at the RP2D in AYA participants (12-39 years) with relapsed or refractory Ewing sarcoma and rhabdomyosarcoma after a maximum of 18 cycles of the combination
Eligibility:
Phase 1
Age >= 12 and <= 39 years of age
Diagnosis of a relapsed or refractory solid tumor and have archival tissue available.
Adequate performance status and adequate major organ function and have recovered from acute toxicity of all prior therapies.
Phase 2
Age >= 12 and <= 39 years of age
Diagnosis of relapsed or refractory Ewing sarcoma or rhabdomyosarcoma and have archival tissue available
Participants must not have received prior combination therapy with irinotecan and temozolomide
Adequate performance status and adequate major organ function and have recovered from acute toxicity of all prior therapies.
Design:
Open label phase 1/2 study to evaluate the safety and preliminary efficacy of PEN-866 given in combination with vincristine and temozolomide in adolescents and young adults with relapsed or refractory solid tumors
Phase 1 portion will use a standard 3 + 3 design with limited dose escalations to define the MTD or the highest safe dose tested of PEN-866 when given in combination with standard dosing of vincristine (1.5 mg/m2 IV on days 1 and 8) and temozolomide (100 mg/m2 orally on days 1-5) given in 21 day cycles
Phase 2 component will use Simon minimax two-stage phase II trial design and will enroll two expansion cohorts of participants (Ewing sarcoma and rhabdomyosarcoma)
For the Ewing sarcoma cohort, up to a total of 25 evaluable participants will be accrued.
For the rhabdomyosarcoma cohort, up to a total of 17 evaluable participants will be accrued.
A potential additional phase 2 expansion cohort may open for enrollment with an amendment if there are participants with diagnoses other than rhabdomyosarcoma or Ewing sarcoma who have demonstrated possible benefit from this combination by experiencing a response in the phase 1 portion of the trial.
Maximum number of treatment cycles is 18.
A maximum of 12 participants will be required to determine the MTD during phase 1, and a maximum of 42 (25+17) evaluable participants will be accrued for the phase 2 cohorts. To allow for a small number of inevaluable participants and to accommodate screen failures, the accrual ceiling will be set at 64.
INCLUSION CRITERIA:
Pathology:
NOTE: Histologic confirmation of original diagnosis or relapse is required by the Laboratory of Pathology, NCI or participating site s Pathology Department. A formalin fixed tissue block or at least 5 unstained slides (10 micron thick) of archival tumor sample must be available at the time of enrollment. Participants under 18 years old without adequate archival tissue available may opt to undergo pre-treatment biopsy if it can be performed with minimal morbidity. In the event that a participants under 18 cannot safely undergo biopsy and does not have adequate archival tissue available, enrollment will be at the discretion of the Study Chair.
Measurable disease:
Prior therapy:
The following prior therapies are permitted, given the indicated time has elapsed:
Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive. At least 21 days must have elapsed after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea).
Anti-cancer agents not known to be myelosuppressive (which can include biologic agent, targeted agent, tyrosine kinase inhibitor, or a metronomic non-myelosuppressive regimen): >=7 days must have elapsed after the last dose of agent.
Antibodies including checkpoint inhibitors: >= 21 days or 3 half-lives (whichever is shorter) must have elapsed from infusion of last dose of antibody.
Systemic corticosteroids: Participants may be on physiologic steroid replacement for adrenal insufficiency or chronic corticosteroids at a stable dose for at least 7 days. Participants undergoing a steroid wean are eligible as long as no dose re-escalation has occurred in the prior 7 days. If steroids are being used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid, unless the participant is receiving physiologic steroid replacement for adrenal insufficiency.
Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g., pegfilgrastim) or 7 days for short-acting growth factor.
Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days must have elapsed after the completion of dose
Stem cell infusions (with or without total body irradiation [TBI]):
XRT/External Beam Irradiation including Protons: >= 84 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial bone marrow radiation. >= 14 days after local XRT however there is no time restriction for palliative radiation with minimal bone marrow involvement and the participant has measurable/evaluable disease outside the radiation port or the site of radiation has documented progression.
Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-MIBG): >= 42 days must have elapsed after systemically administered radiopharmaceutical therapy.
NOTE: Because no dosing or adverse event data are currently available on the use of PEN-866 in participants <18 years of age, children <12 years of age are excluded from this study but will be eligible for future pediatric trials. Since the study population of interest is relapsed or refractory sarcomas which is typically seen in adolescents and young adults, and per FDA recommendations for enrolling adolescents in disease/target-appropriate adult oncology clinical trials of investigational agents, eligibility will include participants aged 12-17 years old.
Hematologic Function:
Peripheral absolute neutrophil count (ANC) >= 1000/mm3
Platelet count >=75,000/mm^3
Hemoglobin >= 8 g/dL
Participants without known metastatic bone marrow disease must meet the blood counts as listed above, without requiring transfusions (defined as not receiving platelet or red blood cell transfusions for at least 7 days prior to initiation of study therapy) or growth factor support
For participants with known metastatic bone marrow disease:
For participants undergoing biopsy only, adequate coagulation defined as INR <= 1.5
Renal Function:
Age 12 to <13 years maximum serum creatine male 1.2 female 1.2
Age 13 to <16 years maximum serum creatine male 1.5 female 1.4
Age >= 16 years maximum serum creatine male 1.7 female 1.4
The Cockcroft-Gault equation should be used for calculation of creatinine clearance.
Liver Function:
Participants with Gilbert s syndrome are excluded from the requirement of a normal bilirubin unless they are found to have the UGT1A1 28/28 genotype. Gilbert s syndrome is found in 3-10% of the general population, and is characterized by mild, chronic unconjugated hyperbilirubinemia in the absence of liver disease or overt hemolysis. NOTE: Adult values will be used for calculating hepatic toxicity and determining eligibility.
Cardiac Function:
Shortening fraction of >=27% or ejection fraction of >= 50% by echocardiogram.
QTc interval < 470 msec
EXCLUSION CRITERIA:
Participants who are receiving any other investigational agents or other anticancer agents.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to PEN-866 (which includes ganetespib or other HSP90 inhibitors, irinotecan, SN-38, or other agents containing irinotecan, SN-38 or its derivatives) or other agents used in study (vincristine and temozolomide).
Participants who have previously discontinued vincristine, temozolomide, or irinotecan due to severe toxicity.
Participants with a history of grade 4 vincristine-related peripheral neuropathy or constipation.
Participants who require medication with any of the inhibitors of UGT1A1, substrates of CYP1A2 or substrates of the P-gp, BCRP, OATP1B1, OATP1B3, or OCT1 transporters. Participants discontinuing these drugs must undergo a washout of 2-weeks or 5 half-lives, whichever is shorter, prior to C1D1.
Uncontrolled intercurrent illness as listed below:
Pregnancy
Major surgery within 28 days prior to start of therapy (C1D1)
UGT1A1 Status
Participants identified with a UGT1A1 28/28 genotype will be excluded from the phase 1 component of the study. In phase 2, they may receive PEN-866 with altered dosing- see Section. Participants who are known to not be homozygous for UGT1A128/28 genotype (i.e., 1/1 or 1/28) may receive the enrolling cohort dose level of PEN-866 on C1D1 during phase 1 and the RP2D of PEN-866 during phase 2.