Clinical Trials /

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

NCT04890093

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.

Related Conditions:
  • Ewing Sarcoma
  • Malignant Solid Tumor
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 10000092
  • SECONDARY ID: 000092-C
  • NCT ID: NCT04890093

Conditions

  • Sarcoma, Ewing
  • Rhabdomyosarcoma

Interventions

DrugSynonymsArms
PEN-8661/Dose Escalation
Vincristine1/Dose Escalation
Temozolomide1/Dose Escalation

Purpose

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.

Detailed Description

      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 subjects 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)
      subjects (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 subjects (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

      Subjects 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 subjects (Ewing sarcoma and rhabdomyosarcoma)

      For the Ewing sarcoma cohort, up to a total of 25 evaluable subjects 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 subjects 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 subjects will be required to determine the MTD during phase 1, and a maximum
      of 42 (25+17) evaluable subjects will be accrued for the phase 2 cohorts. To allow for a
      small number of inevaluable subjects and to accommodate screen failures, the accrual ceiling
      will be set at 64.
    

Trial Arms

NameTypeDescriptionInterventions
1/Dose EscalationExperimentalDose escalation of PEN-866 along with fixed doses of vincristine and temozolomide
  • PEN-866
  • Vincristine
  • Temozolomide
2/MTD/RP2DExperimentalPEN-866 at the MTD or RP2D from phase 1 plus vincristine and temozolomide
  • PEN-866
  • Vincristine
  • Temozolomide

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Pathology:

               -  For phase 1, Subjects must have histologically or cytologically confirmed
                  recurrent or refractory solid tumors, excluding CNS tumors and lymphoma.

               -  For phase 2, subjects must have histologically or cytologically confirmed
                  recurrent or refractory Ewing sarcoma (Cohort 2) or embryonal or alveolar
                  rhabdomyosarcoma (Cohort

          -  Subjects 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. Subjects 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 subject 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, subjects 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, subjects 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, subjects must not have received any prior therapy with an
                  irinotecan/temozolomide combination containing regimen (subjects may have
                  received either drug alone or in combination with different agents at different
                  periods of their course).

               -  For all subjects: Subjects 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.

          -  Corticosteroids: Subjects may be on physiologic steroid replacement for adrenal
             insufficiency or chronic corticosteroids at a stable dose for at least 7 days.
             Subjects 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 subject 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 subject 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

        NOTE: Because no dosing or adverse event data are currently available on the use of PEN-866
        in subjects <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 subjects aged
        12-17 years old.

          -  ECOG performance status <=2, (Karnofsky >=50% for subjects > 16 years of age and
             Lansky >= 50 for subjects <= 16 years of age). NOTE: Neurologic deficits in subjects
             with CNS metastases must have been stable for at least 7 days prior to study
             enrollment. Subjects 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 subject does not
             already have one in place.

          -  Subjects 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 subjects 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 subjects will be eligible for the phase
                            1 component of the study.

                         -  For the phase 2 component, subjects 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 subjects will be excluded from the phase 1
                            component

                    -  For subjects undergoing biopsy only, adequate coagulation defined as INR <=
                       1.5

        Renal Function:

          -  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

        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:

          -  Bilirubin (sum of conjugated + unconjugated) <= 1.5 upper limit of normal (ULN) for
             age

          -  SGPT (ALT) <= 135 U/L.

          -  SGOT (AST) <= 150 U/L.

        Subjects 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

               -  Subjects 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.

               -  Subjects 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. Subjects must be asymptomatic from
                  their brain metastasis and not require corticosteroids for 4 weeks prior to start
                  of therapy (C1D1). Subjects with remote history of spinal cord compression are
                  eligible.

               -  Subjects 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. Subjects 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).

               -  Subjects with human immunodeficiency virus (HIV)-infected subjects on effective
                  anti- retroviral therapy with no detectable viral load on any tests within the
                  last 6 months are eligible for this trial

               -  For subjects with chronic hepatitis B virus (HBV) infection, the HBV viral load
                  must be undetectable on suppressive therapy within the last 6 months.

               -  Subjects with a history of hepatitis C virus (HCV) infection must have been
                  treated and cured. For subjects with HCV infection who are currently on
                  treatment, they are eligible if they have an undetectable HCV viral load within
                  the last 6 months.

               -  If 18 years old or older, must be willing to undergo tumor biopsy before
                  treatment and have available archival tissue. If biopsy is contraindicated,
                  enrollment must be approved by the Study Chair.

               -  Subjects ages 12-17 years old without archival tissue available may opt to
                  undergo pre- treatment biopsy if it can be performed with minimal morbidity. In
                  the event that a subject 12-17 cannot safely undergo biopsy and does not have
                  adequate archival tissue available, enrollment will be at the discretion of the
                  Study Chair.

               -  For women of childbearing potential (WCBP): 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.

               -  Male and female subjects of reproductive 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. 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.

               -  Ability of subject to understand and the willingness to sign a written informed
                  consent document.

        EXCLUSION CRITERIA:

        Subjects 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).

          -  Subjects who have previously discontinued vincristine, temozolomide, or irinotecan due
             to severe toxicity.

          -  Subjects with a history of grade 4 vincristine-related peripheral neuropathy of
             constipation.

          -  Subjects 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. Subjects discontinuing these drugs must undergo a washout of
             2-weeks or 5 half-lives, whichever is shorter, prior to C1D1.

          -  Subjects 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
                  subject 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. Because there is an unknown
             but potential risk for adverse events in nursing infants secondary to treatment of the
             mother with PEN866, breastfeeding should be discontinued if the mother is treated with
             PEN866. These risks also apply to other agents used in this study.

          -  Major surgery within 28 days prior to start of therapy (C1D1)

          -  UGT1A1 Status

        Subjects 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. Subjects 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.
      
Maximum Eligible Age:39 Years
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 2: Objective response rate
Time Frame:baseline to 18 cycles
Safety Issue:
Description:complete response + partial response

Secondary Outcome Measures

Measure:Phase 1: Plasma and tumor pharmacokinetics
Time Frame: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
Safety Issue:
Description:Descriptive report of plasma and tumor pharmacokinetics (PK) of PEN-866 in combination with vincristine and temozolomide
Measure:Phase 1: Toxicity
Time Frame:baseline to 18 cycles
Safety Issue:
Description:Incidence of specific toxicities
Measure:Phase 2: Progression free survival
Time Frame:from start of treatment to time of progression or death
Safety Issue:
Description:Median amount of time subject survives without disease progression after treatment
Measure:Phase 2: Duration of response
Time Frame:baseline to 18 cycles
Safety Issue:
Description:Duration from the date a response is identified until the date of progression or date the response is noted to have ended
Measure:Phase 2: Phospho-gamma-H2AX immunofluorescence
Time Frame:Cycle 1 day 1 and Cycle 1 day 4
Safety Issue:
Description:Levels of phospho-gamma-H2AX immunofluorescence in matched pre- and on-treatment tumor and normal tissue (hair follicle)

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Sarcoma
  • Ewing Sarcoma
  • Rhabdomyosarcoma
  • Small Molecule

Last Updated

May 28, 2021