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 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
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
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
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
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.
Age >= 12 and < 39 years of age
Diagnosis of relapsed or refractory Ewing sarcoma or rhabdomyosarcoma and have archival
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.
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.
- INCLUSION CRITERIA:
- 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
- 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
- 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
- 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
- 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
- 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
- For subjects undergoing biopsy only, adequate coagulation defined as INR <=
- 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.
- Bilirubin (sum of conjugated + unconjugated) <= 1.5 upper limit of normal (ULN) for
- 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.
- 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
- 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
- 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
- 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
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
- 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
- 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
- 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.