Talazoparib Plus Irinotecan With or Without Temozolomide in Children With Refractory or Recurrent Solid Malignancies

NCT02392793 | Completed Phase 1 FDA Drug

• 2 other identifiers: BMNIRNNCI-2015-00255
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 1

Brief Summary

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 cause;
• 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 "apoptosis"). 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.

Conditions

Childhood Solid Tumors

Outcome Measures

Primary Outcomes (4)

• Maximum tolerated dose (MTD) of talazoparib combined with irinotecan

  This study is a traditional dose escalation study using a standard 3+3 phase I design to define the MTD. Six or more dose levels will be evaluated for the combination of talazoparib and irinotecan. Each cycle will last 21 days with talazoparib given daily on days 1-6 and irinotecan given daily on days 2-6.

  After first cycle (21 days) therapy of patients of Arm A.

• Dose-limiting toxicities (DLT) of talazoparib combined with irinotecan

  Dose-limiting toxicities defined in the first cycle of the combination of talazoparib and irinotecan will be summarized for patients treated at each dose level with DLTs type and grade.

  After first cycle (21 days) therapy of patients of Arm A.

• Maximum tolerated dose (MTD) of temozolomide combined with talazoparib

  Once the MTD is defined for the combination of talazoparib plus irinotecan in Arm A, then temozolomide will be added to make a triple drug combination, talazoparib plus irinotecan and temozolomide. This is a traditional dose escalation study using a standard 3+3 phase I design to define the MTD. Six or more dose levels will be evaluated for the combination of talazoparib plus irinotecan and temozolomide. Each cycle will last 21 days with talazoparib given daily on days 1-6 and irinotecan and temozolomide given daily on days 2-6.

  After first cycle (21 days) therapy of patients of Arm B.

• Dose-limited toxicities (DLT) of combination therapy with temozolomide, talazoparib and irinotecan

  DLT defined in the first cycle of the combination of talazoparib plus irinotecan and temozolomide will be summarized for patients treated at each dose level with DLTs type and grade.

  After first cycle (21 days) therapy of patients of Arm B.

Secondary Outcomes (11)

• Response rate

  After 34 cycles of therapy (approximate 24 months).

• Irinotecan Cmax

  days 1 and 5 (week 1) of course 1

• Talazoparib Cmax

  days 1 and 5 (week 1) of course 1

• Irinotecan AUC

  days 1 and 5 (week 1) of course 1

• Talazoparib AUC

  days 1 and 5 (week 1) of course 1

Study Arms (2)

Arm A: Talazoparib Plus Irinotecan

ACTIVE COMPARATOR

Talazoparib will be administered orally on day 1 either once or twice per day depending on the dose level of the enrolled patient. Both oral talazoparib and IV irinotecan will then be administered daily, on days 2-6. Each cycle will last 21 days. Filgrastim or peg-filgrastim will be given following the last dose of chemotherapy. Arm A is closed to enrollment.

Drug: Talazoparib; Drug: Irinotecan; Drug: Filgrastim; Drug: Peg-filgrastim

Arm B: Talazoparib Plus Irinotecan Plus Temozolomide

ACTIVE COMPARATOR

Once the maximum tolerated doses (MTDs) for talazoparib and irinotecan are determined, a second arm of the study will open administering talazoparib, irinotecan and temozolomide. Talazoparib will be given orally, days 1-6. Intravenous irinotecan and oral temozolomide will be given days 2-6. Filgrastim or peg-filgrastim will be given following the last dose of chemotherapy.

Drug: Talazoparib; Drug: Irinotecan; Drug: Temozolomide; Drug: Filgrastim; Drug: Peg-filgrastim

Interventions

Talazoparib DRUG

Given orally once or twice on day 1 (depending on the dose level), then daily on days 2-6.

Also known as: BMN 673

Arm A: Talazoparib Plus Irinotecan; Arm B: Talazoparib Plus Irinotecan Plus Temozolomide

Irinotecan DRUG

Given intravenously daily, days 2-6 immediately following the talazoparib dose.

Also known as: Camptosar®

Arm A: Talazoparib Plus Irinotecan; Arm B: Talazoparib Plus Irinotecan Plus Temozolomide

Temozolomide DRUG

Given orally daily. Dose to be determined after MTD established with talazoparib plus irinotecan.

Also known as: Temodar

Arm B: Talazoparib Plus Irinotecan Plus Temozolomide

Filgrastim DRUG

Given subcutaneously (SubQ) once per day starting 24-36 hours after last dose of chemotherapy and continuing until post-nadir ANC is \>2,000/μL, unless peg-filgrastim is given.

Also known as: G-CSF, Neupogen®

Arm A: Talazoparib Plus Irinotecan; Arm B: Talazoparib Plus Irinotecan Plus Temozolomide

Peg-filgrastim DRUG

Given subcutaneously (SubQ) once per day starting 24-36 hours after last dose of chemotherapy and continuing until post-nadir ANC is \>2,000/μL, unless filgrastim is given.

Also known as: Pegylated filgrastim, Neulasta®

Arm A: Talazoparib Plus Irinotecan; Arm B: Talazoparib Plus Irinotecan Plus Temozolomide

Eligibility Criteria

• Age: 12 Months - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.
• 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 strength(s).
• 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 following parameters:
• 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.

You may not qualify if:

• 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 childbearing potential.
• 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 the pregnancy.
• 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 the study
• 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 eligible.
• 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.

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead
• BioMarin Pharmaceutical: collaborator
• Alliance Pharma: collaborator
• Pfizer: collaborator

Study Sites (1)

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Related Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

MeSH Terms

Interventions

talazoparib; Irinotecan; Temozolomide; Filgrastim; Granulocyte Colony-Stimulating Factor; pegfilgrastim

Intervention Hierarchy (Ancestors)

Camptothecin; Alkaloids; Heterocyclic Compounds; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Study Officials

• Sara M. Federico, MD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 6, 2015
• First Posted: March 19, 2015
• Study Start: March 25, 2015
• Primary Completion: February 20, 2019
• Study Completion: August 30, 2019
• Last Updated: February 9, 2021

Record last verified: 2021-02

Locations

US (1)