The drug, talazoparib, seems to work against cancer in test tubes and animals by preventing
DNA repair in damaged cells leading to their death. Investigators do not know if talazoparib
combined with irinotecan will work in humans. Talazoparib has been used in only a small
number of adults and children, and there is much not yet known about it.
In Arm A of this study, investigators seek to find the safest dose of irinotecan to give
with talazoparib to children and young adults. In a phase I study, different dose levels of
drug may be tested. The first 2 or 3 patients will be given a dose, and if none of them has
a bad side-effect, the next 2 or 3 patients will be given a higher dose. No temozolomide
will be given in in Arm A.
The experimental drug combination of talazoparib and irinotecan will be tested in the hopes
of finding a treatment that may be effective against recurrent or refractory solid tumors.
The goals of study Arm A are:
- To determine whether the combination of talazoparib and irinotecan is a beneficial
treatment for your cancer;
- To learn what kind of side effects talazoparib can cause;
- To learn what kind of side effects talazoparib in combination with irinotecan can
- To learn more about the biology of talazoparib in children diagnosed with solid tumors.
The purpose of Arm B is to to find the safest doses of irinotecan and temozolomide to give
with talazoparib to children and young adults with a solid malignancy.. Talazoparib belongs
to a family of drugs called "poly ADP ribose polymerase or PARP inhibitors." Irinotecan and
temozolomide belong to a family of drugs called "DNA damaging agents."
There are two arms of this trial, A and B. In this study, investigators hope that irinotecan
(administered in Arm A) and irinotecan plus temozolomide (administered in Arm B) will damage
the DNA of the cancer cells. Then, talazoparib (which is a PARP inhibitor) will block the
repair of the cancer cell's damaged DNA, causing the cancer cell to die (a process called
There are different types of cancers found in children and young adults which appear to be
vulnerable to the combination of chemotherapy agents that will be given in this study. Work
carried out in the lab show that these agents may be very promising in the treatment of
ewing sarcoma, germ cell tumors, wilms tumor, medulloblastoma and possibly neuroblastoma.
In Arm A of this study, talazoparib will be administered orally on day 1 either once or
twice per day depending on the dose level of the enrolled participant. Both oral talazoparib
and intravenous (IV) irinotecan will then be administered daily, on days 2-6. Each cycle
will last 21 days.
Once the maximum tolerated doses (MTDs) for talazoparib and irinotecan are determined, a
second arm of the study (Arm B) will open administering talazoparib, irinotecan and
temozolomide. Talazoparib will be given orally, on days 1-6. Intravenous irinotecan and oral
temozolomide will be given on days 2-6. The study will estimate the maximum tolerated doses,
describe the toxicities of therapy, estimate the response rate and characterize the
pharmacokinetics of the combined talazoparib plus irinotecan with or without temozolomide.
This study is a traditional dose escalation study using a standard 3+3 phase I design. In
Arm A, six or more dose levels will be evaluated for the combination of talazoparib and
irinotecan. Once the MTDs of Arm A are determined, Arm B will open and evaluate the
combination of talazoparib, irinotecan and temozolomide.
PRIMARY OBJECTIVES - ARM A
- To estimate the maximum tolerated doses (MTDs) of talazoparib (daily, days 1-6)
combined with irinotecan (daily, days 2-6) given every 21 days in children with
refractory or recurrent solid malignancies.
- To identify and describe the dose limiting toxicities of talazoparib and irinotecan
administered in combination to patients with refractory or recurrent solid
PRIMARY OBJECTIVES - ARM B
- To estimate the maximum tolerated dose (MTD) of temozolomide (given daily, days 2-6)
when combined with talazoparib (daily, days 1-6) and irinotecan (daily, days 2-6) given
every 21 days in children with refractory or recurrent solid malignancies.
- To identify and describe the dose limiting toxicities of temozolomide, talazoparib and
irinotecan administered in combination to patients with refractory or recurrent solid
- To estimate the response rate, within the confines of a phase I study, to talazoparib
plus irinotecan and talazoparib plus irinotecan and temozolomide administered in
combination in pediatric patients with refractory or recurrent solid malignancies.
- To characterize the pharmacokinetics of talazoparib plus irinotecan and talazoparib
plus irinotecan and temozolomide when given in combination to children with refractory
or recurrent solid malignancies.
- Patients with refractory or recurrent solid tumors for which there is no standard
therapy are eligible. Patients must have had histologic verification of malignancy at
original diagnosis or at the time of relapse.
- 12 months - 25 years at the time of enrollment on study.
- Patients must have a BSA of ≥ 0.42 m^2 at the time of study enrollment due to capsule
- Patients must have either measureable or evaluable disease.
- Life expectancy must be at least 8 weeks.
- Performance status: Karnofsky ≥ 50 for patients > 16 years of age; Lansky ≥ 50 for
patients ≤ 16 years of age.
- Prior therapy: Patients who have received prior therapy with an irinotecan-based or
temozolomide-based regimen are eligible. Patients who have received prior therapy
with a PARP inhibitor other than talazoparib are eligible; however, patients who have
progressed on a PARP inhibitor plus irinotecan regimen are not eligible.
- Organ function: Must have adequate organ and bone marrow function as defined by the
- Patients with solid tumors not metastatic to bone marrow:
- Peripheral absolute neutrophil count (ANC) ≥1,000/mm^3
- Platelet count ≥ 100,000/mm^3 (no transfusion within 7 days of enrollment)
- Hemoglobin ≥ 9 g/dL (with or without support)
- Patients with solid tumors metastatic to bone marrow will be eligible for study
but not evaluable for hematologic toxicity. These patients must not be known to
be refractory to red cell or platelet transfusions. At least 2 of every cohort
of 3 patients must be evaluable for hematologic toxicity. If dose limiting
hematologic toxicity is observed at any dose level, all subsequent patients
enrolled must be evaluable for hematologic toxicity.
- Adequate renal function defined as: Serum creatinine concentration ≤3x the
institutional upper limit of normal (ULN) or creatinine clearance or
radioisotope GFR ≥ 70ml/min/1.73m^2.
- Adequate liver function defined as: For Part A participants: normal liver
function as defined by SGPT (ALT) concentration ≤5x the institutional ULN, a
total bilirubin concentration ≤2x the institutional ULN for age, and serum
albumin ≥ 2g/dL.
- Adequate liver function defined as: For Part B participants: normal liver
function as defined by SGPT (ALT) concentration < 2.5 times institutional ULN, a
total bilirubin concentration ≤ 1.5 times the institutional ULN for age, and
serum albumin ≥ 2 g/dL.
- Patients must have fully recovered from the acute toxic effects of chemotherapy,
immunotherapy, surgery, or radiotherapy prior to entering this study:
- Myelosuppressive chemotherapy: Patient has not received myelosuppressive
chemotherapy within 3 weeks of enrollment onto this study (6 weeks if prior
- Hematopoietic growth factors: At least 7 days must have elapsed since the
completion of therapy with a growth factor. At least 14 days must have elapsed
after receiving pegfilgrastim.
- Biologic (anti-neoplastic agent): At least 7 days must have elapsed since
completion of therapy with a biologic agent. For agents that have known adverse
events occurring beyond 7 days after administration, this period prior to
enrollment must be extended beyond the time during which adverse events are
known to occur.
- Monoclonal antibodies: At least 3 half-lives must have elapsed since prior
therapy that included a monoclonal antibody.
- Radiotherapy: At least 2 weeks must have elapsed since any irradiation; at least
6 weeks must have elapsed since craniospinal RT or substantial bone marrow
- All patients and/or their parents or legally authorized representatives must sign a
written informed consent. Assent will be obtained, when appropriate, according to
- Pregnant or breastfeeding.
- If sexually active and with childbearing potential, must agree to use effective
method of contraception, such as intrauterine device, bilateral tubal ligation
for ≥ 6 months before randomization, partner vasectomized for ≥ 6 months before
randomization, and sexual abstinence when in relation to the preferred and usual
lifestyle of the subject.
- Male subjects must use a condom when having sex with a pregnant woman and when
having sex with a woman of childbearing potential from the time of the first
dose of study drug through 105 days after the last dose of study drug.
- Contraception should be considered for a nonpregnant female partner of
- Male subjects with partners of childbearing potential must use a condom and
contraception should be considered for the female partner from the time of the
first dose of study drug through 105 days after the last dose of study drug.
- Male subjects whose partners are pregnant should use condoms for the duration of
- Male and female subjects must agree not to donate sperm or eggs, respectively,
from the first dose of study drug through 105 days and 45 days after the last
dose of study drug, respectively (hormonal contraception is not allowed) prior
to study entry, during treatment, and for 45 days after last dose of study drug.
- Females considered not of childbearing potential include those who are
surgically sterile (bilateral salpingectomy, bilateral oophorectomy, or
hysterectomy) or who are post menopausal, defined as: < 55 years of age with no
spontaneous menses for ≥ 12 months before randomization and with a
postmenopausal follicle stimulating hormone (FSH) concentration > 30 IU/L (or
meeting criteria for post-menopausal status by the local laboratory).
- If females with childbearing potential, a negative serum pregnancy test at
Screening and willing to have additional serum and urine pregnancy tests during
- Note: Females without childbearing potential include those in menopause ≥2
years, with tubal ligation ≥1 year before screening, or with total hysterectomy.
- Concomitant medications
- Corticosteroids: Patients receiving corticosteroids that have not been on a
stable or decreasing dose for at least 7 days prior to enrollment are not
- Investigational drugs: Patients cannot receive other investigational drugs while
on this study.
- Anti-GVHD drugs post-transplant: Patients receiving cyclosporine, tacrolimus or
other GVHD agents are not eligible.
- Prior treatment with talazoparib.
- Unable to swallow capsules.
- Active, uncontrolled infection.
- Prior solid organ transplant.
- Prior total body irradiation (TBI).
- Unwilling or unable to comply with the safety monitoring requirements of this