Talazoparib and Temozolomide in Treating Younger Patients With Refractory or Recurrent Malignancies

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of
temozolomide when combined with a dose of talazoparib (BMN 673) given once daily for 5 days
after a one day dose of BMN 673 administered orally (either once daily or twice daily), every
28 days to children with refractory or recurrent solid tumors. (Phase I) II. To define and
describe the toxicities of BMN 673 given with temozolomide administered on this schedule.
(Phase I) III. To characterize the pharmacokinetics of BMN 673 and temozolomide when given in
combination to children with refractory or recurrent cancer. (Phase I) IV. To define the
antitumor activity of BMN 673 when given with temozolomide in recurrent/refractory Ewing
sarcoma and recurrent acute lymphoblastic leukemia (ALL). (Phase II)

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of BMN 673 and temozolomide in pediatric
patients with recurrent or refractory solid tumors within the confines of a phase I study.

II. To explore possible predictive biomarkers in archival tumor tissue from Ewing sarcoma
patients in Phase II.

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients receive talazoparib orally (PO) once daily (QD) or twice daily (BID) on days 1-6 and
temozolomide PO QD on days 2-6. Treatment repeats every 28 days for up to 24 courses in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Inclusion Criteria:

- Age:

- Phase 1 (Part A)

- Patients must be > than 12 months and =< 21 years of age at the time of
study enrollment

- Phase 2 (Part B and Part C)

- Patients must be > than 12 months and =< 30 years of age at the time of
study enrollment

- Body surface area (for Parts A, B and C):

- Patients must have a body surface area (BSA) of >= 0.42 m^2 at the time of study
enrollment

- Diagnosis:

- Phase 1 (Part A)

- Solid tumors (Part A1): patients with relapsed or refractory solid tumors
including central nervous system (CNS) tumors without bone marrow
involvement are eligible; patients must have had histologic verification of
malignancy at original diagnosis or relapse except in patients with
intrinsic brain stem tumors, optic pathway gliomas, or patients with pineal
tumors and elevations of cerebrospinal fluid (CSF) or serum tumor markers
including alpha-fetoprotein or beta-human chorionic gonadotropin (HCG)

- Ewing sarcoma or peripheral primitive neuroectodermal tumor (PNET) (Part
A2): patients with relapsed or refractory Ewing sarcoma or peripheral PNET
without bone marrow involvement will be eligible for Part A2 if there are no
available slots on Part A1; these patients will be enrolled at one dose
level below the dose level at which patients on Part A1 are actively
enrolling, or at the starting dose level (dose level 1) if dose escalation
has not yet occurred; patients must have had histologic verification of
malignancy at original diagnosis or relapse

- Phase 2 (Part B)

- Ewing sarcoma or peripheral PNET: patients with relapsed or refractory Ewing
sarcoma or peripheral PNET are eligible; patients must have had histologic
verification of malignancy at original diagnosis or relapse

- Phase 2 (Part C)

- Acute lymphoblastic leukemias (ALL): patients must have 2nd or greater
relapse of pre-B ALL or T-cell ALL; patients may not have refractory disease

- Patients with ALL must have had histologic verification of the malignancy at
the most recent relapse, including immunophenotyping to confirm diagnosis

- Disease status:

- Phase 1 (Part A):

- Patients must have either measurable or evaluable disease

- Phase 2 (Part B):

- Ewing sarcoma or peripheral PNET: patients must have measurable disease

- Phase 2 (Part C):

- Acute lymphoblastic leukemias (ALL): patients with ALL must have an M3
marrow with or without extramedullary site of relapse OR an M2 bone marrow
with an extramedullary site of relapse; patients with CNS 3 status are not
eligible for enrollment

- Therapeutic options: patient's current disease state must be one for which there is no
known curative therapy or therapy proven to prolong survival with an acceptable
quality of life

- Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16
years of age; Note: neurologic deficits in patients with CNS tumors must have been
relatively stable for at least 7 days prior to study enrollment; patients who are
unable to walk because of paralysis, but who are up in a wheelchair, will be
considered ambulatory for the purpose of assessing the performance score

- Patients who have received prior therapy with a temozolomide-based regimen are
eligible; Note: patients who have progressed on a poly adenosine diphosphate ribose
polymerase (PARP) inhibitor and temozolomide regimen are not eligible for Part A of
the study

- Patients must have fully recovered from the acute toxic effects of all prior
anti-cancer chemotherapy

- Myelosuppressive chemotherapy:

- Solid tumors (Part A and Part B): at least 21 days after the last dose of
myelosuppressive chemotherapy (42 days if prior nitrosourea)

- Acute lymphoblastic leukemias (ALL) (Part C):

- Patients with leukemia who relapse while receiving standard maintenance
chemotherapy will not be required to have a waiting period before
enrollment onto this study

- Patients who relapse while they are not receiving standard maintenance
therapy, must have fully recovered from all acute toxic effects of
prior therapy; at least 14 days must have elapsed after the completion
of cytotoxic therapy, with the exception of hydroxyurea

- Note: cytoreduction with hydroxyurea can be initiated and continued for
up to 24 hours prior to the start of BMN 673

- Note: patients with leukemia are permitted to receive intrathecal
chemotherapy, including methotrexate or cytarabine; intrathecal therapy
should be restricted to days 15 and 22 of each 28 day cycle

- Hematopoietic growth factors: at least 14 days after the last dose of a
long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth
factor; for agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which adverse
events are known to occur; the duration of this interval must be discussed with
the study chair

- Biologic (anti-neoplastic agent): at least 7 days after the last dose of a
biologic agent; for agents that have known adverse events occurring beyond 7 days
after administration, this period must be extended beyond the time during which
adverse events are known to occur; the duration of this interval must be
discussed with the study chair

- Immunotherapy: at least 42 days after the completion of any type of
immunotherapy, e.g. tumor vaccines

- Monoclonal antibodies: at least 3 half-lives of the antibody after the last dose
of a monoclonal antibody

- Radiation therapy (XRT): at least 14 days after local palliative XRT (small
port); at least 42 days must have elapsed if other substantial bone marrow (BM)
radiation; patients with prior total body irradiation (TBI), craniospinal XRT
and/or >= 50% radiation of the pelvis are not eligible

- Stem cell infusion without TBI: no evidence of active graft vs. host disease and
at least 84 days must have elapsed after transplant or stem cell infusion

- PARP inhibitor exposure:

- Part A: Patients who have received prior therapy with a PARP inhibitor, with the
exception of BMN 673, are eligible; however, patients who have progressed on a
PARP inhibitor and temozolomide regimen are not eligible

- Part B and Part C: Patients who have previously been exposed to a PARP inhibitor
are not eligible

- For patients with solid tumors without known bone marrow involvement: peripheral
absolute neutrophil count (ANC) >= 1000/mm^3

- For patients with solid tumors without known bone marrow involvement: platelet count
>= 100,000/mm^3 (transfusion independent, defined as not receiving platelet
transfusions for at least 7 days prior to enrollment)

- For patients with solid tumors without known bone marrow involvement: hemoglobin >=
8.0 g/dL (may receive red blood cell [RBC] transfusions)

- All patients enrolled on Part A of the study must be evaluable for hematologic
toxicity

- Patients on Part B of the study with known bone marrow metastatic disease will be
eligible for the study provided they meet the blood counts (may receive transfusions
provided they are not known to be refractory to red cell or platelet transfusions);
these patients will not be evaluable for hematologic toxicity

- Patients on Part C with acute lymphoblastic leukemia: platelet count >= 20,000/mm^3
(may receive platelet transfusions); these patients must not be known to be refractory
to red cell or platelet transfusion

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
ml/min/1.73 m^2 or a maximum serum creatinine (mg/dL) based on age/gender as follows:

- 1 to < 2 years: 0.6

- 2 to < 6 years: 0.8

- 6 to < 10 years: 1

- 10 to < 13 years: 1.2

- 13 to < 16 years: 1.5 for males, 1.4 for females

- >= 16 years: 1.7 for males, 1.4 for females

- Patients on Part A and Part B: bilirubin (sum of conjugated + unconjugated) =< 1.5 x
upper limit of normal (ULN) for age

- Patients on Part A and Part B: serum glutamate pyruvate transaminase (SGPT) (alanine
aminotransferase [ALT]) =< 110 U/L; for the purpose of this study, the ULN for SGPT is
45 U/L

- Patients on Part A and Part B: serum albumin >= 2 g/dL

- Patients on Part C with ALL: bilirubin (sum of conjugated + unconjugated) =< 1.5 x ULN
for age

- Patients on Part C with ALL: SGPT (ALT) =< 225 U/L; for the purpose of this study, the
ULN for SGPT is 45 U/L

- Patients on Part C with ALL: serum albumin >= 2 g/dL

- All patients and/or their parents or legally authorized representatives must sign a
written informed consent; assent, when appropriate, will be obtained according to
institutional guidelines

- For patients enrolling on Part B: tissue blocks or slides must be sent; if tissue
blocks or slides are unavailable, the Study Chair must be notified prior to enrollment

Exclusion Criteria:

- Pregnant or breast-feeding women will not be entered on this study; pregnancy tests
must be obtained in girls who are post-menarchal; males or females of reproductive
potential may not participate unless they have agreed to use an effective
contraceptive method

- Patients receiving corticosteroids who have not been on a stable or decreasing dose of
corticosteroid for at least 7 days prior to enrollment are not eligible

- Patients who are currently receiving another investigational drug are not eligible

- Patients who are currently receiving other anti-cancer agents are not eligible (except
leukemia patients receiving hydroxyurea, which may be continued until 24 hours prior
to start of protocol therapy); patients with acute lymphoblastic leukemia may receive
intrathecal therapy

- Patients who are receiving cyclosporine, tacrolimus or other agents to prevent
graft-versus-host disease post bone marrow transplant are not eligible for this trial

- Patients must be able to swallow capsules whole

- Patients who have an uncontrolled infection are not eligible

- For Part C (Phase 2): recurrent ALL patients with CNS 3 status are not eligible

- Patients who have received a prior solid organ transplantation are not eligible

- Patients with prior TBI, craniospinal XRT and/or those with >= 50% radiation of the
pelvis are not eligible

- Patients who in the opinion of the investigator may not be able to comply with the
safety monitoring requirements of the study are not eligible

- Patients with known hypersensitivity to temozolomide or dacarbazine are not eligible

- Phase 1 (Part A): patients who have progressed on a PARP inhibitor and temozolomide
regimen are not eligible

- Phase 2 (Part B and Part C): patients who have previously been exposed to a PARP
inhibitor are not eligible

- Phase 1 (Part A): patients with known bone marrow involvement are not eligible