Accepts Healthy Volunteers
Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms
An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.
An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.
Searching Both is inclusive of interventional and observational studies.
|Eligible Ages||12 Years - 39 Years|
INCLUSION 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).
- - Measurable disease: - For phase 1, participants must have measurable (per RECIST 1.1.
- - 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.
- - 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.
- - 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.
- - Corticosteroids: Participants may be on physiologic steroid replacement for adrenal insufficiency or chronic corticosteroids at a stable dose for at least 7 days.
- - 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.
- - 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.
- - 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: Hematologic Function: - Peripheral absolute neutrophil count (ANC) >= 1000/mm3.
- - Platelet count >=75,000/mm^3.
- - Hemoglobin >= 8 g/dL.
- - 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.
- - For participants undergoing biopsy only, adequate coagulation defined as INR <= 1.5.
- - Creatinine clearance* or radioisotope GFR (Bullet) 60 mL/min/1.73 m^2 or.
- - A serum creatinine based on age/gender as follows: Age 12 to <13 years maximum serum creatine male 1.2 female 1.2.
- - 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 with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate t is not required and is unlikely to be required during the first cycle of therapy.
- - 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.
- - If 18 years old or older, must be willing to undergo tumor biopsy before treatment and have available archival tissue.
- - Participants ages 12-17 years old without archival tissue available may opt to undergo pre- treatment biopsy if it can be performed with minimal morbidity.
- - For women of childbearing potential (WCBP): negative serum Beta human chorionic gonadotropin (Beta hCG) pregnancy test during screening.
- - Male and female 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.
- - Ability of 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 of 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, or any prohibited medications.
- - Participants with known bone marrow metastatic disease causing decreased blood counts below the hematologic parameters are excluded from the phase 1 component due to the in ability to be evaluable for hematologic toxicity, however they are eligible for phase 2, with transfusion support.
- - 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.
- - Pregnant women are excluded from this study because the effects of PEN-866 on the developing human fetus are unknown, and vincristine and temozolomide are cytotoxic chemotherapeutic agents which are known to be teratogenic.
- - Major surgery within 28 days prior to start of therapy (C1D1) - UGT1A1 Status.
This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.
Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.
Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.
Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.
Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.
|Phase 1/Phase 2|
The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.
|National Cancer Institute (NCI)|
The person who is responsible for the scientific and technical direction of the entire clinical study.
|Christine M Heske, M.D.|
|Principal Investigator Affiliation||National Cancer Institute (NCI)|
Category of organization(s) involved as sponsor (and collaborator) supporting the trial.
|Overall Status||Not yet recruiting|
The disease, disorder, syndrome, illness, or injury that is being studied.
|Sarcoma, Ewing, Rhabdomyosarcoma|
|Study Website:||View Trial Website|
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 subjects 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.
Experimental: 1/Dose Escalation
Dose escalation of PEN-866 along with fixed doses of vincristine and temozolomide
PEN-866 at the MTD or RP2D from phase 1 plus vincristine and temozolomide
Drug: - PEN-866
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.
Drug: - Vincristine
Vincristine will be given at a dose of 1.5 mg/m2 by IV on days 1 and 8 of each 21-day cycle
Drug: - Temozolomide
temozolomide will be given at a dose of 100 mg/m2, orally on days 1-5, of each 21-day cycle
Contact a Trial Team
If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.