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NCT02116777

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

Completed Phase 1, PHASE2 Results posted Last updated 26 March 2021
What this trial tests

Phase 1, PHASE2 trial testing Laboratory Biomarker Analysis in Adult Solid Neoplasm in 40 participants. Completed in 31 December 2018.

Timeline
16 May 2014
Primary endpoint
31 December 2018
31 December 2018

Quick facts

Lead sponsorNational Cancer Institute (NCI)
PhasePhase 1, PHASE2
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designsequential
Maskingnone
Primary purposetreatment
Enrollment40
Start date16 May 2014
Primary completion31 December 2018
Estimated completion31 December 2018
Sites22 locations across United States

Drugs / interventions tested

Conditions studied

Sponsor

National Cancer Institute (NCI)

Who can join

Adults 13 Months to 30, any sex, with Adult Solid Neoplasm or Childhood Solid Neoplasm. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

The Number of Participants With Dose Limiting Toxicities to Determine the Maximum Tolerated Dose of Temozolomide and Talazoparib Combination Therapy Primary · 28 days

The Maximum Tolerated Dose (MTD) reflects the highest dose of Talazoparib (BMN 673) when combined with a dose of temozolomide that did not cause a Grade 3 or higher toxicity in children with refractory or recurrent solid tumors.

GroupValue95% CI
400 mcg/m²/Dose BMN 673 QD+20mg/m²/Dose TEM,Max 800 mcg/Day0
400 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 800 mcg/Day0
600 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 1000 mcg/Day1
600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM, Max 1000 mcg/Day2
600 mcg/m²/Dose BMN 673 BID+40mg/m²/Dose TEM, Max 1000 mcg/Day2
600 mcg/m²/doseBMN 673 BID+55mg/m²/Dose TEM, Max 1000 mcg/Day2
600 mcg/m²/Dose BMN 673 BID+30 mg/m²/Dose TEM,Max 1000 mcg/Day0
All Cycle 1 Toxicities >=Grade 3 Primary · Up to 28 days

The number of patients with at least one toxicity (DLT or non-DLT) in cycle 1 that is at least possibly attributable to study agent

GroupValue95% CI
400 mcg/m²/Dose BMN 673 QD+20mg/m²/Dose TEM,Max 800 mcg/Day0
400 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 800 mcg/Day0
600 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 1000 mcg/Day2
600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM, Max 1000 mcg/Day7
600 mcg/m²/Dose BMN 673 BID+40mg/m²/Dose TEM, Max 1000 mcg/Day5
600 mcg/m²/doseBMN 673 BID+55mg/m²/Dose TEM, Max 1000 mcg/Day3
600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM,Max 1000 mcg/Day5
T Max of Talazoparib Primary · Cycle 1 Day 1 pre-dose, and 1, 2, 4, 8 and 24 hours after the first talazoparib dose.

Median with minimum and maximum for the time at which the maximum (peak) serum concentration occurs.

GroupValue95% CI
Treatment (Talazoparib, Temozolomide): Phase 121 – 24
C Max of Talazoparib Primary · Cycle 1 Day 1 pre-dose, and 1, 2, 4, 8 and 24 hours after the first talazoparib dose.

Median with minimum and maximum for the time at which the maximum (peak) serum concentration occurs.

GroupValue95% CI
Treatment (Talazoparib, Temozolomide): Phase 14670708 – 19300
AUC of Talazoparib Primary · Cycle 1 Day 1 pre-dose, and 1, 2, 4 and 8 hours after the first talazoparib dose

Median with minimum and maximum for the area under the drug concentration over time curve.

GroupValue95% CI
Treatment (Talazoparib, Temozolomide): Phase 117.552.15 – 63.14
Accumulation Half-life of Talazoparib in Combination With Temozolomide. Primary · Cycle 1 Day 1 pre-dose, and 1, 2, 4 and 8 hours after the first talazoparib dose. Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the talazoparib dose

Median with minimum and maximum for the time required for the serum concentration to fall to 50% of its starting dose.

GroupValue95% CI
Treatment (Talazoparib, Temozolomide): Phase 146.818.20 – 253.27
T Max of Talazoparib in Combination With Temozolomide Primary · Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the talazoparib dose

Median with minimum and maximum for the time at which the maximum (peak) serum concentration occurs.

GroupValue95% CI
Treatment (Talazoparib, Temozolomide): Phase 11.041 – 8
C Max of Talazoparib in Combination With Temozolomide Primary · Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the talazoparib dose

Median with minimum and maximum for the time at which the maximum (peak) serum concentration occurs.

GroupValue95% CI
Treatment (Talazoparib, Temozolomide): Phase 1164507070 – 56300
AUC of Talazoparib in Combination With Temozolomide Primary · Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the talazoparib dose

Median with minimum and maximum area under the drug concentration over time curve

GroupValue95% CI
Treatment (Talazoparib, Temozolomide): Phase 182.0841.92 – 226.70
AUC of Talazoparib in Combination With Temozolomide Primary · Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the talazoparib dose

Median with minimum and maximum area under the drug concentration over time curve

GroupValue95% CI
Treatment (Talazoparib, Temozolomide): Phase 1173.0883.61 – 456.28
Clearance of Talazoparib in Combination With Temozolomide Primary · Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the talazoparib dose

Median with minimum and maximum for the rate of elimination of the drug.

GroupValue95% CI
Treatment (Talazoparib, Temozolomide): Phase 13.081.34 – 6.19
Accumulation Ratio of Talazoparib in Combination With Temozolomide Primary · Cycle 1 Day 1 pre-dose, and 1, 2, 4 and 8 hours after the first talazoparib dose. Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the talazoparib dose

Median with minimum and maximum of the accumulation ratio.

GroupValue95% CI
Treatment (Talazoparib, Temozolomide): Phase 13.341.67 – 15.73

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to 24 months. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

400 mcg/m²/Dose BMN 673 QD+20mg/m²/Dose TEM,Max 800 mcg/Day
Serious: 2/3 (67%)
Deaths: 0/3
400 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 800 mcg/Day
Serious: 2/3 (67%)
Deaths: 0/3
600 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 1000 mcg/Day
Serious: 2/3 (67%)
Deaths: 0/3
600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM, Max 1000 mcg/Day
Serious: 11/13 (85%)
Deaths: 2/13
600 mcg/m²/Dose BMN 673 BID+40mg/m²/Dose TEM, Max 1000 mcg/Day
Serious: 6/6 (100%)
Deaths: 1/6
600 mcg/m²/doseBMN 673 BID+55mg/m²/Dose TEM, Max 1000 mcg/Day
Serious: 3/3 (100%)
Deaths: 0/3
600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM,Max 1000 mcg/Day
Serious: 8/9 (89%)
Deaths: 0/9

Serious adverse events (72 terms)

ReactionSystem400 mcg/m²/Dose BMN 673 QD…400 mcg/m²/Dose BMN 673 BI…600 mcg/m²/Dose BMN 673 BI…600 mcg/m²/Dose BMN 673 BI…600 mcg/m²/Dose BMN 673 BI…600 mcg/m²/doseBMN 673 BID…600 mcg/m²/Dose BMN 673 BI…
Neutrophil count decreasedInvestigations
Lymphocyte count decreasedInvestigations
AnemiaBlood and lymphatic system disorders
Platelet count decreasedInvestigations
White blood cell decreasedInvestigations
Activated partial thromboplastin time prolongedInvestigations
HypokalemiaMetabolism and nutrition disorders
SeizureNervous system disorders
Abdominal painGastrointestinal disorders
Alanine aminotransferase increasedInvestigations
AnorexiaMetabolism and nutrition disorders
AnxietyPsychiatric disorders
Aspartate aminotransferase increasedInvestigations
AtaxiaNervous system disorders
Catheter related infectionInfections and infestations
DysarthriaNervous system disorders
DysphagiaGastrointestinal disorders
DysphasiaNervous system disorders
DyspneaRespiratory, thoracic and mediastinal disorders
Ear painEar and labyrinth disorders
Edema faceGeneral disorders
Febrile neutropeniaBlood and lymphatic system disorders
FeverGeneral disorders
GGT increasedInvestigations
Gait disturbanceGeneral disorders
Other adverse events (257 terms — click to expand)

ReactionSystem400 mcg/m²/Dose BMN 673 QD…400 mcg/m²/Dose BMN 673 BI…600 mcg/m²/Dose BMN 673 BI…600 mcg/m²/Dose BMN 673 BI…600 mcg/m²/Dose BMN 673 BI…600 mcg/m²/doseBMN 673 BID…600 mcg/m²/Dose BMN 673 BI…
AnemiaBlood and lymphatic system disorders
FatigueGeneral disorders
Lymphocyte count decreasedInvestigations
White blood cell decreasedInvestigations
Platelet count decreasedInvestigations
Alkaline phosphatase increasedInvestigations
AnorexiaMetabolism and nutrition disorders
NauseaGastrointestinal disorders
Neutrophil count decreasedInvestigations
AlopeciaSkin and subcutaneous tissue disorders
Aspartate aminotransferase increasedInvestigations
ConstipationGastrointestinal disorders
DiarrheaGastrointestinal disorders
Facial nerve disorderNervous system disorders
HeadacheNervous system disorders
HyperglycemiaMetabolism and nutrition disorders
HypermagnesemiaMetabolism and nutrition disorders
HypoalbuminemiaMetabolism and nutrition disorders
Pain in extremityMusculoskeletal and connective tissue disorders
Sinus tachycardiaCardiac disorders
VomitingGastrointestinal disorders
Alanine aminotransferase increasedInvestigations
AnxietyPsychiatric disorders
Creatinine increasedInvestigations
HyponatremiaMetabolism and nutrition disorders
HypophosphatemiaMetabolism and nutrition disorders
Non-cardiac chest painGeneral disorders
AtaxiaNervous system disorders
Back painMusculoskeletal and connective tissue disorders
Blood bilirubin increasedInvestigations
CoughRespiratory, thoracic and mediastinal disorders
DizzinessNervous system disorders
DyspneaRespiratory, thoracic and mediastinal disorders
Edema limbsGeneral disorders
EpistaxisRespiratory, thoracic and mediastinal disorders
FeverGeneral disorders
HypocalcemiaMetabolism and nutrition disorders
Muscle weakness right-sidedMusculoskeletal and connective tissue disorders
PainGeneral disorders
ProteinuriaRenal and urinary disorders

Most-reported serious reactions: Neutrophil count decreased, Lymphocyte count decreased, Anemia, Platelet count decreased, White blood cell decreased, Activated partial thromboplastin time prolonged, Hypokalemia, Seizure.

Data from ClinicalTrials.gov NCT02116777 adverse events section.

Sponsor's own description

This phase I/II trial studies the side effects and best dose of talazoparib and temozolomide and to see how well they work in treating younger patients with tumors that have not responded to previous treatment (refractory) or have come back (recurrent). Talazoparib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving talazoparib together with temozolomide may work better in treating younger patients with refractory or recurrent malignancies.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Synergistic activity of PARP inhibition by talazoparib (BMN 673) with temozolomide in pediatric cancer models in the pediatric preclinical testing program.
    Smith MA, Reynolds CP, Kang MH, Kolb EA, et al · · 2015 · cited 99× · PMID 25500058 · DOI 10.1158/1078-0432.ccr-14-2572
  2. Current status of poly(ADP-ribose) polymerase inhibitors and future directions.
    Ohmoto A, Yachida S. · · 2017 · cited 96× · PMID 29138572 · DOI 10.2147/ott.s139336
  3. Inhibitors of PARP: Number crunching and structure gazing.
    Rudolph J, Jung K, Luger K. · · 2022 · cited 86× · PMID 35259019 · DOI 10.1073/pnas.2121979119
  4. An update on PARP inhibitors for the treatment of cancer.
    Benafif S, Hall M. · · 2015 · cited 78× · PMID 25750544 · DOI 10.2147/ott.s30793
  5. Molecular mechanisms underpinning sarcomas and implications for current and future therapy.
    Damerell V, Pepper MS, Prince S. · · 2021 · cited 75× · PMID 34188019 · DOI 10.1038/s41392-021-00647-8
  6. Management of recurrent Ewing sarcoma: challenges and approaches.
    Van Mater D, Wagner L. · · 2019 · cited 71× · PMID 30988632 · DOI 10.2147/ott.s170585
  7. Restricted Delivery of Talazoparib Across the Blood-Brain Barrier Limits the Sensitizing Effects of PARP Inhibition on Temozolomide Therapy in Glioblastoma.
    Kizilbash SH, Gupta SK, Chang K, Kawashima R, et al · · 2017 · cited 64× · PMID 28947502 · DOI 10.1158/1535-7163.mct-17-0365
  8. Combinations of PARP Inhibitors with Temozolomide Drive PARP1 Trapping and Apoptosis in Ewing's Sarcoma.
    Gill SJ, Travers J, Pshenichnaya I, Kogera FA, et al · · 2015 · cited 64× · PMID 26505995 · DOI 10.1371/journal.pone.0140988

Verify or expand the search:

Other trials of Laboratory Biomarker Analysis

Trials testing the same drug.

Other recruiting trials for Adult Solid Neoplasm

Currently open trials in the same condition.

Other National Cancer Institute (NCI) trials

Trials by the same sponsor.

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Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing