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

NCT04890093 | Suspended Phase 1 FDA Drug

• 2 other identifiers: 10000092000092-C
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Sarcoma, Ewing; Rhabdomyosarcoma

Keywords

Sarcoma; Ewing Sarcoma; Rhabdomyosarcoma; Small Molecule

Outcome Measures

Primary Outcomes (2)

• Phase 2: Objective response rate

  complete response + partial response

  baseline to 18 cycles

• Phase 1: Maximum tolerated/recommended phase 2 dose

  toxicity type/grade and the fraction of patients with a DLT at each dose level

  baseline to 18 cycles

Secondary Outcomes (5)

• Phase 1: Plasma and tumor pharmacokinetics

  pre/post infusion on Cycle 1 Day 1, 24 hr post infusion, Cycle 1 Day 4, Cycle 1 Day 8. Cycle 3 Day 1 and Cycle 3 day 8

• Phase 1: Toxicity

  baseline to 18 cycles

• Phase 2: Progression free survival

  from start of treatment to time of progression or death

• Phase 2: Duration of response

  baseline to 18 cycles

• Phase 2: Phospho-gamma-H2AX immunofluorescence

  Cycle 1 day 1 and Cycle 1 day 4

Study Arms (2)

1/Dose Escalation

EXPERIMENTAL

Dose escalation of PEN-866 along with fixed doses of vincristine and temozolomide

Drug: PEN-866; Drug: Vincristine; Drug: Temozolomide

2/MTD/RP2D

EXPERIMENTAL

PEN-866 at the MTD or RP2D from phase 1 plus vincristine and temozolomide

Drug: PEN-866; Drug: Vincristine; Drug: Temozolomide

Interventions

PEN-866 DRUG

PEN-866 will be given as an IV infusion once every week for the first two consecutive weeks out of every three-week (21 day) cycle.

1/Dose Escalation; 2/MTD/RP2D

Vincristine DRUG

Vincristine will be given at a dose of 1.5 mg/m2 by IV on days 1 and 8 of each 21-day cycle

1/Dose Escalation; 2/MTD/RP2D

Temozolomide DRUG

temozolomide will be given at a dose of 100 mg/m2, orally on days 1-5, of each 21-day cycle

1/Dose Escalation; 2/MTD/RP2D

Eligibility Criteria

• Age: 12 Years - 39 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.
• 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:
• 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.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (2)

Childrens National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Sarcoma, Ewing; Rhabdomyosarcoma; Sarcoma

Interventions

Vincristine; Temozolomide

Condition Hierarchy (Ancestors)

Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Myosarcoma; Neoplasms, Muscle Tissue

Intervention Hierarchy (Ancestors)

Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring

Study Officials

• Christine M Heske, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 15, 2021
• First Posted: May 18, 2021
• Study Start: October 31, 2024
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2027
• Last Updated: March 16, 2026

Record last verified: 2026-02-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. Genomic data are made available via dbGaP through requests to the data custodians.

Locations

US (2)