- -
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.
- - 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.
- - 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 (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.
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 t 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.
- - 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.
- - 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.
In
the event that a participant 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 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.
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 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 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 discontinuing these drugs must undergo a
washout of 2-weeks or 5 half-lives, whichever is shorter, prior to C1D1.
- - 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.
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.
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.
