- -
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).
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.
- - 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.
NOTE: Because no dosing or adverse event data are currently available on the use of
PEN-866 in participants <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 participants aged 12-17 years old.
- - 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:
Hematologic Function:
- Peripheral absolute neutrophil count (ANC) >= 1000/mm3.
- - Platelet count >=75,000/mm^3.
- - 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.
Renal Function:
- - Creatinine clearance or radioisotope GFR >= 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.
Participants 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.
- - 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.
EXCLUSION CRITERIA:
- - 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.
- - Major surgery within 28 days prior to start of therapy (C1D1)
- UGT1A1 Status.
Participants 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. Participants 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.
