SUSPENDED

Vincristine and Temozolomide in Combination With PEN-866 for Adolescents and Young Adults With Relapsed or Refractory Solid Tumors

Conditions

Sarcoma, Ewing Rhabdomyosarcoma Sarcoma Ewing Sarcoma Small Molecule

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

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.

Official Title

Phase 1/2 Study of Vincristine and Temozolomide in Combination With PEN-866 for Adolescents and Young Adults With Relapsed or Refractory Solid Tumors

Quick Facts

Study Start:2024-10-31

Study Completion:2027-12-31

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:SUSPENDED

Study ID

NCT04890093

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:12 Years to 39 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:CHILD, ADULT

Inclusion Criteria	Exclusion Criteria
* Pathology: * For phase 1, Participants must have histologically or cytologically confirmed recurrent or refractory solid tumors, excluding CNS tumors and lymphoma. * For phase 2, participants must have histologically or cytologically confirmed recurrent or refractory Ewing sarcoma (Cohort 2) or embryonal or alveolar rhabdomyosarcoma (Cohort 3). Participants with Ewing sarcoma (Cohort 2 only) should have evidence of EWS translocation by FISH or RT-PCR. * Measurable disease: * For phase 1, participants must have measurable (per RECIST 1.1.) or non-measurable disease on imaging, or presence of recurrent/residual disease identified on aspirate/biopsy or due to presence of elevated tumor biomarkers. * For phase 2, participants must have measurable disease, per RECIST 1.1. * Prior therapy: * For phase 1, there are no limits to the number of prior treatment regimens * For phase 2, there are no limits to the number of prior treatment regimens. However, participants must not have received any prior therapy with an irinotecan/temozolomide combination containing regimen (participants may have received either drug alone or in combination with different agents at different periods of their course). * For all participants: Participants must have recovered from the acute side effects of their prior therapy, such that eligibility criteria are met. * 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 \[TBI\]): * Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including DLI or boost infusion: \>= 84 days must have elapsed after infusion and no evidence of GVHD. * Autologous stem cell infusion including boost infusion: \>= 42 days must have elapsed. * Cellular Therapy: \>= 42 days must have elapsed after the completion of any type of cellular therapy (e.g., modified T cells, NK cells, dendritic cells, etc.). * 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. * Age \>= 12 years and \<= 39 years * ECOG performance status \<=2, (Karnofsky \>=50% for participants \> 16 years of age and Lansky \>= 50% for participants \<= 16 years of age. NOTE: Neurologic deficits in participants with CNS metastases must have been stable for at least 7 days prior to study enrollment. Participants who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of performance. * Willingness to have a central venous access line placed if the participant does not already have one in place. * Participants must have adequate organ and marrow function as defined below: * 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: * Provided they 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 these participants will be eligible for the phase 1 component of the study. * For the phase 2 component, participants should meet the blood counts as listed above, but may receive transfusions of red blood cells or platelets provided they are not known to be refractory to red cell or platelet transfusions. These participants will be excluded from the phase 1 component. * For participants undergoing biopsy only, adequate coagulation defined as INR \<= 1.5 * Creatinine clearance or radioisotope GFR \>= 60 mL/min/1.73 m\^2 or * A serum creatinine based on age/gender as follows: * Bilirubin (sum of conjugated + unconjugated) \<= 1.5 upper limit of normal (ULN) for age * SGPT (ALT) \<= 135 U/L. * SGOT (AST) \<= 150 U/L. * Shortening fraction of \>=27% or ejection fraction of \>= 50% by echocardiogram. * QTc interval \< 470 msec * Participants with toxicities from prior therapies must have resolution of these toxicities to \<= Grade 1, with the exception of peripheral neuropathy and alopecia which must resolve to \<=Grade 2. * Participants with treated brain metastases (CNS as primary tumor not eligible) are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression. Participants must be asymptomatic from their brain metastasis and not require corticosteroids for 4 weeks prior to start of therapy (C1D1). Participants with remote history of spinal cord compression are eligible. * Participants with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy. Participants must be asymptomatic or have disease controlled with surgery and radiation and should not require steroids within 4 weeks prior to start of therapy (C1D1). * Participants with human immunodeficiency virus (HIV)-infected participants on effective anti- retroviral therapy with no detectable viral load on any tests within the last 6 months are eligible for this trial * For participants with chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy within the last 6 months. * Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load within the last 6 months. * Participants ages 18 years old and older must be willing to undergo tumor biopsy before treatment and have available archival tissue (specifically, a formalin fixed tissue block or at least 5 unstained slides \[10 micron thick\]) at the time of enrollment. If biopsy is contraindicated or unable to be performed and/or there is no archival tissue available, enrollment must be approved by the Study Chair. * Participants ages 12-17 years old without available archival tissue (specifically, a formalin fixed tissue block or at least 5 unstained slides \[10 micron thick\]) at the time of enrollment may opt to undergo pre-treatment biopsy if it is clinically indicated or if it can be performed with minimal morbidity using local anesthesia. In the event that a participant 12-17 cannot undergo biopsy as described above and does not have adequate archival tissue available, enrollment will be at the discretion of the Study Chair. * Individuals of childbearing potential: negative serum Beta human chorionic gonadotropin ((Beta)hCG) pregnancy test during screening. A negative pregnancy test is also required within 8 days before first treatment; screening results may be used for treatment if they fall within the required window. * Participants of reproductive potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from the time of consent, for the duration of therapy, and for 6 months after the last dose of study therapy. * Nursing participants must be willing to discontinue nursing from study treatment initiation through 6 months after completion of chemotherapy * Ability of participant (or parent or legal guardian in case of pediatric participant) to understand and the willingness to sign a written informed consent document.	* 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: * Unstable angina within 6 months prior to start of treatment * Myocardial infarction within 6 months prior to start of treatment * New York Heart Association Class III - IV heart failure * Clinically important abnormalities in rhythm, conduction, or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block) * Congenital long QT syndrome * Uncontrolled hypertension despite use of antihypertensives for management of hypertension * Stroke or transient ischemic attack within 6 months prior to start of treatment * As judged by the investigator, evidence of severe or uncontrolled systemic disease, active bleeding diatheses, renal or liver transplant, or Grade \>2 active infection * Any medical, psychological, or social condition that would interfere with the participant s participation in the study. * Any other uncontrolled intercurrent systemic illness that would limit compliance with study requirements * Pregnancy * Major surgery within 28 days prior to start of therapy (C1D1) * UGT1A1 Status

Inclusion Criteria

Exclusion Criteria

* Pathology:
* For phase 1, Participants must have histologically or cytologically confirmed recurrent or refractory solid tumors, excluding CNS tumors and lymphoma.
* For phase 2, participants must have histologically or cytologically confirmed recurrent or refractory Ewing sarcoma (Cohort 2) or embryonal or alveolar rhabdomyosarcoma (Cohort 3). Participants with Ewing sarcoma (Cohort 2 only) should have evidence of EWS translocation by FISH or RT-PCR.
* Measurable disease:
* For phase 1, participants must have measurable (per RECIST 1.1.) or non-measurable disease on imaging, or presence of recurrent/residual disease identified on aspirate/biopsy or due to presence of elevated tumor biomarkers.
* For phase 2, participants must have measurable disease, per RECIST 1.1.
* Prior therapy:
* For phase 1, there are no limits to the number of prior treatment regimens
* For phase 2, there are no limits to the number of prior treatment regimens. However, participants must not have received any prior therapy with an irinotecan/temozolomide combination containing regimen (participants may have received either drug alone or in combination with different agents at different periods of their course).
* For all participants: Participants must have recovered from the acute side effects of their prior therapy, such that eligibility criteria are met.
* 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 \[TBI\]):
* Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including DLI or boost infusion: \>= 84 days must have elapsed after infusion and no evidence of GVHD.
* Autologous stem cell infusion including boost infusion: \>= 42 days must have elapsed.
* Cellular Therapy: \>= 42 days must have elapsed after the completion of any type of cellular therapy (e.g., modified T cells, NK cells, dendritic cells, etc.).
* 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.
* Age \>= 12 years and \<= 39 years
* ECOG performance status \<=2, (Karnofsky \>=50% for participants \> 16 years of age and Lansky \>= 50% for participants \<= 16 years of age. NOTE: Neurologic deficits in participants with CNS metastases must have been stable for at least 7 days prior to study enrollment. Participants who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of performance.
* Willingness to have a central venous access line placed if the participant does not already have one in place.
* Participants must have adequate organ and marrow function as defined below:
* 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:
* Provided they 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 these participants will be eligible for the phase 1 component of the study.
* For the phase 2 component, participants should meet the blood counts as listed above, but may receive transfusions of red blood cells or platelets provided they are not known to be refractory to red cell or platelet transfusions. These participants will be excluded from the phase 1 component.
* For participants undergoing biopsy only, adequate coagulation defined as INR \<= 1.5
* Creatinine clearance or radioisotope GFR \>= 60 mL/min/1.73 m\^2 or
* A serum creatinine based on age/gender as follows:
* Bilirubin (sum of conjugated + unconjugated) \<= 1.5 upper limit of normal (ULN) for age
* SGPT (ALT) \<= 135 U/L.
* SGOT (AST) \<= 150 U/L.
* Shortening fraction of \>=27% or ejection fraction of \>= 50% by echocardiogram.
* QTc interval \< 470 msec
* Participants with toxicities from prior therapies must have resolution of these toxicities to \<= Grade 1, with the exception of peripheral neuropathy and alopecia which must resolve to \<=Grade 2.
* Participants with treated brain metastases (CNS as primary tumor not eligible) are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression. Participants must be asymptomatic from their brain metastasis and not require corticosteroids for 4 weeks prior to start of therapy (C1D1). Participants with remote history of spinal cord compression are eligible.
* Participants with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy. Participants must be asymptomatic or have disease controlled with surgery and radiation and should not require steroids within 4 weeks prior to start of therapy (C1D1).
* Participants with human immunodeficiency virus (HIV)-infected participants on effective anti- retroviral therapy with no detectable viral load on any tests within the last 6 months are eligible for this trial
* For participants with chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy within the last 6 months.
* Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load within the last 6 months.
* Participants ages 18 years old and older must be willing to undergo tumor biopsy before treatment and have available archival tissue (specifically, a formalin fixed tissue block or at least 5 unstained slides \[10 micron thick\]) at the time of enrollment. If biopsy is contraindicated or unable to be performed and/or there is no archival tissue available, enrollment must be approved by the Study Chair.
* Participants ages 12-17 years old without available archival tissue (specifically, a formalin fixed tissue block or at least 5 unstained slides \[10 micron thick\]) at the time of enrollment may opt to undergo pre-treatment biopsy if it is clinically indicated or if it can be performed with minimal morbidity using local anesthesia. In the event that a participant 12-17 cannot undergo biopsy as described above and does not have adequate archival tissue available, enrollment will be at the discretion of the Study Chair.
* Individuals of childbearing potential: negative serum Beta human chorionic gonadotropin ((Beta)hCG) pregnancy test during screening. A negative pregnancy test is also required within 8 days before first treatment; screening results may be used for treatment if they fall within the required window.
* Participants of reproductive potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from the time of consent, for the duration of therapy, and for 6 months after the last dose of study therapy.
* Nursing participants must be willing to discontinue nursing from study treatment initiation through 6 months after completion of chemotherapy
* Ability of participant (or parent or legal guardian in case of pediatric participant) to understand and the willingness to sign a written informed consent document.

* 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:
* Unstable angina within 6 months prior to start of treatment
* Myocardial infarction within 6 months prior to start of treatment
* New York Heart Association Class III - IV heart failure
* Clinically important abnormalities in rhythm, conduction, or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block)
* Congenital long QT syndrome
* Uncontrolled hypertension despite use of antihypertensives for management of hypertension
* Stroke or transient ischemic attack within 6 months prior to start of treatment
* As judged by the investigator, evidence of severe or uncontrolled systemic disease, active bleeding diatheses, renal or liver transplant, or Grade \>2 active infection
* Any medical, psychological, or social condition that would interfere with the participant s participation in the study.
* Any other uncontrolled intercurrent systemic illness that would limit compliance with study requirements
* Pregnancy
* Major surgery within 28 days prior to start of therapy (C1D1)
* UGT1A1 Status

Contacts and Locations

Principal Investigator

Christine M Heske, M.D.

PRINCIPAL_INVESTIGATOR

National Cancer Institute (NCI)

Study Locations (Sites)

Childrens National Medical Center

Washington D.C., District of Columbia, 20010

United States

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892

United States

Collaborators and Investigators

Sponsor: National Cancer Institute (NCI)

Christine M Heske, M.D., PRINCIPAL_INVESTIGATOR, National Cancer Institute (NCI)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2024-10-31

Study Completion Date2027-12-31

Study Record Updates

Study Start Date2024-10-31

Study Completion Date2027-12-31

Terms related to this study

Keywords Provided by Researchers

Sarcoma
Ewing Sarcoma
Rhabdomyosarcoma
Small Molecule

Additional Relevant MeSH Terms

Sarcoma, Ewing
Rhabdomyosarcoma