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

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Completed
CT.gov ID
NCT02116777
Collaborator
(none)
40
Enrollment
22
Locations
2
Arms
55.5
Actual Duration (Months)
1.8
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:
  1. 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.(Phase II)
SECONDARY OBJECTIVES:

  1. 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.

  2. 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.

Study Design

Study Type:
Interventional
Actual Enrollment :
40 participants
Allocation:
Randomized
Intervention Model:
Sequential Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1/2 Study of BMN 673, an Oral Poly(ADP-Ribose) Polymerase Inhibitor, Plus Temozolomide in Children With Refractory or Recurrent Malignancies
Actual Study Start Date :
May 16, 2014
Actual Primary Completion Date :
Dec 31, 2018
Actual Study Completion Date :
Dec 31, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (talazoparib, temozolomide): Phase 1

(Part A): Patients receive talazoparib PO QD or 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.

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Pharmacological Study
Correlative studies

Drug: Talazoparib
Given PO
Other Names:
  • BMN 673
  • BMN-673

    • Drug: Temozolomide
    Given PO
    Other Names:
  • CCRG-81045
  • Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-
  • M & B 39831
  • M and B 39831
  • Methazolastone
  • RP-46161
  • SCH 52365
  • Temcad
  • Temodal
  • Temodar
  • Temomedac
  • TMZ

    		•
    Experimental: Treatment (talazoparib, temozolomide): Phase 2

    (Part B): Relapse/Refractory EWS or PNET Patients receive MTD from Phase 1 portion of study. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

    Other: Laboratory Biomarker Analysis
    Correlative studies

    Other: Pharmacological Study
    Correlative studies

    Drug: Talazoparib
    Given PO
    Other Names:
  • BMN 673
  • BMN-673

    • Drug: Temozolomide
    Given PO
    Other Names:
  • CCRG-81045
  • Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-
  • M & B 39831
  • M and B 39831
  • Methazolastone
  • RP-46161
  • SCH 52365
  • Temcad
  • Temodal
  • Temodar
  • Temomedac
  • TMZ

    		•

    Outcome Measures

    Primary Outcome Measures

    1. The Number of Participants With Dose Limiting Toxicities to Determine the Maximum Tolerated Dose of Temozolomide and Talazoparib Combination Therapy [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.

    2. All Cycle 1 Toxicities >=Grade 3 [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

    3. T Max of Talazoparib [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.

    4. C Max of Talazoparib [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.

    5. AUC of Talazoparib [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.

    6. Accumulation Half-life of Talazoparib in Combination With Temozolomide. [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.

    7. T Max of Talazoparib in Combination With Temozolomide [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.

    8. C Max of Talazoparib in Combination With Temozolomide [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.

    9. AUC of Talazoparib in Combination With Temozolomide [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

    10. Clearance of Talazoparib in Combination With Temozolomide [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.

    11. Accumulation Ratio of Talazoparib in Combination With Temozolomide [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.

    12. Half-life of Temozolomide in Combination With Talazoparib [Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the temozolomide dose]

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

    13. T Max of Temozolomide in Combination With Talazoparib [Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the temozolomide dose]

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

    14. C Max of Temozolomide in Combination With Talazoparib [Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the temozolomide dose]

      Median with minimum and maximum for the maximum (peak) serum concentration.

    15. AUC of Temozolomide in Combination With Talazoparib [Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the temozolomide dose.]

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

    16. Clearance of Temozolomide in Combination With Talazoparib [Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the temozolomide dose]

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

    17. Number of Ewing/Peripheral PNET Participants in Phase 2 With Complete Response (CR) or Partial Response (PR) [Up to 24 months]

      Frequency of Ewing sarcoma and peripheral PNET participants with Complete Response (CR) or Partial Response (PR) per the Response Evaluation Criteria In Solid Tumors (RECIST)

    Secondary Outcome Measures

    1. Number of Solid Tumor Patients With Complete Response (CR) or Partial Response (PR) [Up to 24 months]

      Frequency of solid tumor participants with Complete Response (CR) or Partial Response (PR) per the Response Evaluation Criteria In Solid Tumors (RECIST)

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    13 Months to 30 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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)

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

    • Body surface area (for Parts A and B):

    • 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)

    • 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

    • 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)

    • 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: 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

    • 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

    • 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

    • 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): 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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Children's Hospital of Alabama Birmingham Alabama United States 35233
    2 Children's Hospital Los Angeles Los Angeles California United States 90027
    3 Children's Hospital of Orange County Orange California United States 92868
    4 UCSF Medical Center-Parnassus San Francisco California United States 94143
    5 UCSF Medical Center-Mission Bay San Francisco California United States 94158
    6 Children's Hospital Colorado Aurora Colorado United States 80045
    7 Children's National Medical Center Washington District of Columbia United States 20010
    8 Children's Healthcare of Atlanta - Egleston Atlanta Georgia United States 30322
    9 Lurie Children's Hospital-Chicago Chicago Illinois United States 60611
    10 Riley Hospital for Children Indianapolis Indiana United States 46202
    11 C S Mott Children's Hospital Ann Arbor Michigan United States 48109
    12 University of Minnesota/Masonic Cancer Center Minneapolis Minnesota United States 55455
    13 Washington University School of Medicine Saint Louis Missouri United States 63110
    14 NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center New York New York United States 10032
    15 Cincinnati Children's Hospital Medical Center Cincinnati Ohio United States 45229
    16 Oregon Health and Science University Portland Oregon United States 97239
    17 Children's Hospital of Philadelphia Philadelphia Pennsylvania United States 19104
    18 Children's Hospital of Pittsburgh of UPMC Pittsburgh Pennsylvania United States 15224
    19 St. Jude Children's Research Hospital Memphis Tennessee United States 38105
    20 Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center Houston Texas United States 77030
    21 Seattle Children's Hospital Seattle Washington United States 98105
    22 Children's Hospital of Wisconsin Milwaukee Wisconsin United States 53226

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Eric S Schafer, COG Phase I Consortium

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT02116777
    Other Study ID Numbers:
    • NCI-2014-00804
    • NCI-2014-00804
    • ADVL1411
    • ADVL1411
    • UM1CA097452
    First Posted:
    Apr 17, 2014
    Last Update Posted:
    Mar 26, 2021
    Last Verified:
    Mar 1, 2021
    Additional relevant MeSH terms:
    Neoplasms
    Sarcoma, Ewing
    Neuroectodermal Tumors
    Neuroectodermal Tumors, Primitive
    Neuroectodermal Tumors, Primitive, Peripheral
    Nervous System Neoplasms
    Central Nervous System Neoplasms
    Recurrence
    Temozolomide
    Talazoparib

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail Patients receive talazoparib PO QD or 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.
    Arm/Group Title 400 mcg/m²/Dose BMN 673 QD+20mg/m²/Dose TEM,Max 800 mcg/Day 400 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 800 mcg/Day 600 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+40mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/doseBMN 673 BID+55mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM,Max 1000 mcg/Day
    Arm/Group Description Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 2: Part B Part B: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET (Phase 2)
    Period Title: Overall Study
    STARTED 3 3 3 13 6 3 9
    COMPLETED 0 0 0 0 0 0 0
    NOT COMPLETED 3 3 3 13 6 3 9

    Baseline Characteristics

    Arm/Group Title 400 mcg/m²/Dose BMN 673 QD+20mg/m²/Dose TEM,Max 800 mcg/Day 400 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 800 mcg/Day 600 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+40mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/doseBMN 673 BID+55mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM,Max 1000 mcg/Day Total
    Arm/Group Description Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 2: Part B Part B: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET (Phase 2) Total of all reporting groups
    Overall Participants 3 3 3 13 6 3 9 40
    Age (Count of Participants)
    <=18 years
    2
    66.7%
    2
    66.7%
    3
    100%
    12
    92.3%
    5
    83.3%
    3
    100%
    3
    33.3%
    30
    75%
    Between 18 and 65 years
    1
    33.3%
    1
    33.3%
    0
    0%
    1
    7.7%
    1
    16.7%
    0
    0%
    6
    66.7%
    10
    25%
    >=65 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Age (Years) [Median (Full Range) ]
    Median (Full Range) [Years]
    18
    16
    14
    13
    13.5
    12
    22
    15.5
    Sex: Female, Male (Count of Participants)
    Female
    1
    33.3%
    1
    33.3%
    1
    33.3%
    3
    23.1%
    4
    66.7%
    2
    66.7%
    4
    44.4%
    16
    40%
    Male
    2
    66.7%
    2
    66.7%
    2
    66.7%
    10
    76.9%
    2
    33.3%
    1
    33.3%
    5
    55.6%
    24
    60%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    2
    66.7%
    1
    33.3%
    2
    15.4%
    0
    0%
    0
    0%
    1
    11.1%
    6
    15%
    Not Hispanic or Latino
    3
    100%
    1
    33.3%
    2
    66.7%
    11
    84.6%
    6
    100%
    2
    66.7%
    7
    77.8%
    32
    80%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    1
    11.1%
    2
    5%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    1
    33.3%
    1
    7.7%
    0
    0%
    0
    0%
    0
    0%
    2
    5%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    1
    33.3%
    0
    0%
    0
    0%
    2
    15.4%
    1
    16.7%
    0
    0%
    0
    0%
    4
    10%
    White
    2
    66.7%
    3
    100%
    2
    66.7%
    7
    53.8%
    5
    83.3%
    2
    66.7%
    8
    88.9%
    29
    72.5%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    3
    23.1%
    0
    0%
    1
    33.3%
    1
    11.1%
    5
    12.5%

    Outcome Measures

    1. Primary Outcome
    Title The Number of Participants With Dose Limiting Toxicities to Determine the Maximum Tolerated Dose of Temozolomide and Talazoparib Combination Therapy
    Description 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.
    Time Frame 28 days

    Outcome Measure Data

    Analysis Population Description
    Patients with toxicity grade 3 or above.
    Arm/Group Title 400 mcg/m²/Dose BMN 673 QD+20mg/m²/Dose TEM,Max 800 mcg/Day 400 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 800 mcg/Day 600 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+40mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/doseBMN 673 BID+55mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30 mg/m²/Dose TEM,Max 1000 mcg/Day
    Arm/Group Description Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Part PK
    Measure Participants 3 3 3 7 6 3 6
    Count of Participants [Participants]
    0
    0%
    0
    0%
    1
    33.3%
    2
    15.4%
    2
    33.3%
    2
    66.7%
    0
    0%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 400 mcg/m²/Dose BMN 673 QD+20mg/m²/Dose TEM,Max 800 mcg/Day, 400 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 800 mcg/Day, 600 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 1000 mcg/Day, 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM, Max 1000 mcg/Day, 600 mcg/m²/Dose BMN 673 BID+40mg/m²/Dose TEM, Max 1000 mcg/Day, 600 mcg/m²/doseBMN 673 BID+55mg/m²/Dose TEM, Max 1000 mcg/Day, 600 mcg/m²/Dose BMN 673 BID+30 mg/m²/Dose TEM,Max 1000 mcg/Day
    Comments
    Type of Statistical Test Other
    Comments Maximum Tolerate Dose Level was determined by the rolling-6 design.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Maximum Tolerate Dose Level
    Estimated Value 4
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments Maximum Tolerate Dose Level is Dose Level 4 (600 mcg/m²/dose +30 mg/m2/dose (BMN 673) BID + 30 mg/m²/dose (TEM), Max 1000 mcg/day). MTD determined by using the Rolling-6 Design.
    2. Primary Outcome
    Title All Cycle 1 Toxicities >=Grade 3
    Description 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
    Time Frame Up to 28 days

    Outcome Measure Data

    Analysis Population Description
    Patients with toxicity grade 3 or above.
    Arm/Group Title 400 mcg/m²/Dose BMN 673 QD+20mg/m²/Dose TEM,Max 800 mcg/Day 400 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 800 mcg/Day 600 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+40mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/doseBMN 673 BID+55mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM,Max 1000 mcg/Day
    Arm/Group Description Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 2: Part B Part B: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET (Phase 2)
    Measure Participants 3 3 3 13 6 3 9
    Count of Participants [Participants]
    0
    0%
    0
    0%
    2
    66.7%
    7
    53.8%
    5
    83.3%
    3
    100%
    5
    55.6%
    3. Primary Outcome
    Title T Max of Talazoparib
    Description Median with minimum and maximum for the time at which the maximum (peak) serum concentration occurs.
    Time Frame Cycle 1 Day 1 pre-dose, and 1, 2, 4, 8 and 24 hours after the first talazoparib dose.

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) studies were completed for all but 3 patients in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
    Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
    Arm/Group Description (Part A): Patients receive talazoparib PO QD or 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. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Talazoparib: Given PO Temozolomide: Given PO
    Measure Participants 28
    Median (Full Range) [Hours]
    2
    4. Primary Outcome
    Title C Max of Talazoparib
    Description Median with minimum and maximum for the time at which the maximum (peak) serum concentration occurs.
    Time Frame Cycle 1 Day 1 pre-dose, and 1, 2, 4, 8 and 24 hours after the first talazoparib dose.

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) studies were completed for all but 3 patients in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
    Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
    Arm/Group Description (Part A): Patients receive talazoparib PO QD or 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. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Talazoparib: Given PO Temozolomide: Given PO
    Measure Participants 28
    Median (Full Range) [ng/mL]
    4670
    5. Primary Outcome
    Title AUC of Talazoparib
    Description Median with minimum and maximum for the area under the drug concentration over time curve.
    Time Frame Cycle 1 Day 1 pre-dose, and 1, 2, 4 and 8 hours after the first talazoparib dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) studies were completed for all but 4 patients in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
    Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
    Arm/Group Description (Part A): Patients receive talazoparib PO QD or 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. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Talazoparib: Given PO Temozolomide: Given PO
    Measure Participants 27
    Median (Full Range) [h•µg/L]
    17.55
    6. Primary Outcome
    Title Accumulation Half-life of Talazoparib in Combination With Temozolomide.
    Description Median with minimum and maximum for the time required for the serum concentration to fall to 50% of its starting dose.
    Time Frame 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

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) studies were completed for all but 4 patients in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
    Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
    Arm/Group Description (Part A): Patients receive talazoparib PO QD or 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. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Talazoparib: Given PO Temozolomide: Given PO
    Measure Participants 27
    Median (Full Range) [Hours]
    46.8
    7. Primary Outcome
    Title T Max of Talazoparib in Combination With Temozolomide
    Description Median with minimum and maximum for the time at which the maximum (peak) serum concentration occurs.
    Time Frame Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the talazoparib dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) studies were completed for all but 3 patients in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
    Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
    Arm/Group Description (Part A): Patients receive talazoparib PO QD or 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. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Talazoparib: Given PO Temozolomide: Given PO
    Measure Participants 28
    Median (Full Range) [Hours]
    1.04
    8. Primary Outcome
    Title C Max of Talazoparib in Combination With Temozolomide
    Description Median with minimum and maximum for the time at which the maximum (peak) serum concentration occurs.
    Time Frame Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the talazoparib dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) studies were completed for all but 3 patients in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
    Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
    Arm/Group Description (Part A): Patients receive talazoparib PO QD or 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. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Talazoparib: Given PO Temozolomide: Given PO
    Measure Participants 28
    Median (Full Range) [pg/ml]
    16450
    9. Primary Outcome
    Title AUC of Talazoparib in Combination With Temozolomide
    Description Median with minimum and maximum area under the drug concentration over time curve
    Time Frame Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the talazoparib dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) studies were completed for all but 3 patients in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
    Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
    Arm/Group Description (Part A): Patients receive talazoparib PO QD or 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. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Talazoparib: Given PO Temozolomide: Given PO
    Measure Participants 28
    Median (Full Range) [h•µg/L]
    82.08
    10. Primary Outcome
    Title AUC of Talazoparib in Combination With Temozolomide
    Description Median with minimum and maximum area under the drug concentration over time curve
    Time Frame Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the talazoparib dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) studies were completed for all but 3 patients in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
    Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
    Arm/Group Description (Part A): Patients receive talazoparib PO QD or 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. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Talazoparib: Given PO Temozolomide: Given PO
    Measure Participants 28
    Median (Full Range) [h•µg/L]
    173.08
    11. Primary Outcome
    Title Clearance of Talazoparib in Combination With Temozolomide
    Description Median with minimum and maximum for the rate of elimination of the drug.
    Time Frame Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the talazoparib dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) studies were completed for all but 3 patients in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
    Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
    Arm/Group Description (Part A): Patients receive talazoparib PO QD or 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. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Talazoparib: Given PO Temozolomide: Given PO
    Measure Participants 28
    Median (Full Range) [L/hr/m²]
    3.08
    12. Primary Outcome
    Title Accumulation Ratio of Talazoparib in Combination With Temozolomide
    Description Median with minimum and maximum of the accumulation ratio.
    Time Frame 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

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) studies were completed for all but 4 patients in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
    Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
    Arm/Group Description (Part A): Patients receive talazoparib PO QD or 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. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Talazoparib: Given PO Temozolomide: Given PO
    Measure Participants 27
    Median (Full Range) [Ratio]
    3.34
    13. Primary Outcome
    Title Half-life of Temozolomide in Combination With Talazoparib
    Description Median with minimum and maximum for the time required for the serum concentration to fall to 50% of its starting dose.
    Time Frame Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the temozolomide dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) studies were completed for all but 1 patient in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
    Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
    Arm/Group Description (Part A): Patients receive talazoparib PO QD or 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. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Talazoparib: Given PO Temozolomide: Given PO
    Measure Participants 30
    Median (Full Range) [Hours]
    1.74
    14. Primary Outcome
    Title T Max of Temozolomide in Combination With Talazoparib
    Description Median with minimum and maximum for the time at which the maximum (peak) serum concentration occurs.
    Time Frame Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the temozolomide dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) studies were completed for all but 1 patient in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
    Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
    Arm/Group Description (Part A): Patients receive talazoparib PO QD or 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. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Talazoparib: Given PO Temozolomide: Given PO
    Measure Participants 30
    Median (Full Range) [Hours]
    1.03
    15. Primary Outcome
    Title C Max of Temozolomide in Combination With Talazoparib
    Description Median with minimum and maximum for the maximum (peak) serum concentration.
    Time Frame Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the temozolomide dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) studies were completed for all but 1 patient in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
    Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
    Arm/Group Description (Part A): Patients receive talazoparib PO QD or 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. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Talazoparib: Given PO Temozolomide: Given PO
    Measure Participants 30
    Median (Full Range) [ng/mL]
    1234.1
    16. Primary Outcome
    Title AUC of Temozolomide in Combination With Talazoparib
    Description Median with minimum and maximum for the area under the drug concentration over time curve.
    Time Frame Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the temozolomide dose.

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) studies were completed for all but 1 patient in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
    Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
    Arm/Group Description (Part A): Patients receive talazoparib PO QD or 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. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Talazoparib: Given PO Temozolomide: Given PO
    Measure Participants 30
    Median (Full Range) [h•µg/L]
    4352.16
    17. Primary Outcome
    Title Clearance of Temozolomide in Combination With Talazoparib
    Description Median with minimum and maximum for the rate of elimination of the drug.
    Time Frame Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the temozolomide dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) studies were completed for all but 1 patient in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
    Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
    Arm/Group Description (Part A): Patients receive talazoparib PO QD or 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. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Talazoparib: Given PO Temozolomide: Given PO
    Measure Participants 30
    Median (Full Range) [L/hr/m²]
    6.49
    18. Primary Outcome
    Title Number of Ewing/Peripheral PNET Participants in Phase 2 With Complete Response (CR) or Partial Response (PR)
    Description Frequency of Ewing sarcoma and peripheral PNET participants with Complete Response (CR) or Partial Response (PR) per the Response Evaluation Criteria In Solid Tumors (RECIST)
    Time Frame Up to 24 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 2
    Arm/Group Description (Part B): Relapse/Refractory EWS or PNET Patients receive MTD from Phase 1 portion of study. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Talazoparib: Given PO Temozolomide: Given PO
    Measure Participants 9
    Count of Participants [Participants]
    0
    0%
    19. Secondary Outcome
    Title Number of Solid Tumor Patients With Complete Response (CR) or Partial Response (PR)
    Description Frequency of solid tumor participants with Complete Response (CR) or Partial Response (PR) per the Response Evaluation Criteria In Solid Tumors (RECIST)
    Time Frame Up to 24 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
    Arm/Group Description (Part A): Patients receive talazoparib PO QD or 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. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Talazoparib: Given PO Temozolomide: Given PO
    Measure Participants 31
    Count of Participants [Participants]
    1
    33.3%

    Adverse Events

    Time Frame Up to 24 months
    Adverse Event Reporting Description Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.
    Arm/Group Title 400 mcg/m²/Dose BMN 673 QD+20mg/m²/Dose TEM,Max 800 mcg/Day 400 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 800 mcg/Day 600 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+40mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/doseBMN 673 BID+55mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM,Max 1000 mcg/Day
    Arm/Group Description Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 1: Part A Part A1: Patients with relapsed or refractory solid tumors and CNS tumors Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET Phase 2: Part B Part B: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET (Phase 2)
    All Cause Mortality
    400 mcg/m²/Dose BMN 673 QD+20mg/m²/Dose TEM,Max 800 mcg/Day 400 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 800 mcg/Day 600 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+40mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/doseBMN 673 BID+55mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM,Max 1000 mcg/Day
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/13 (15.4%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Serious Adverse Events
    400 mcg/m²/Dose BMN 673 QD+20mg/m²/Dose TEM,Max 800 mcg/Day 400 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 800 mcg/Day 600 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+40mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/doseBMN 673 BID+55mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM,Max 1000 mcg/Day
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/3 (66.7%) 2/3 (66.7%) 2/3 (66.7%) 11/13 (84.6%) 6/6 (100%) 3/3 (100%) 8/9 (88.9%)
    Blood and lymphatic system disorders
    Anemia 0/3 (0%) 0/3 (0%) 0/3 (0%) 3/13 (23.1%) 1/6 (16.7%) 2/3 (66.7%) 5/9 (55.6%)
    Febrile neutropenia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 1/3 (33.3%) 1/9 (11.1%)
    Cardiac disorders
    Sinus tachycardia 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Ear and labyrinth disorders
    Ear pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Eye disorders
    Optic nerve disorder 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Gastrointestinal disorders
    Abdominal pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 1/9 (11.1%)
    Dysphagia 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Intra-abdominal hemorrhage 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Nausea 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 1/9 (11.1%)
    Typhlitis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Vomiting 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    General disorders
    Edema face 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Fever 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Gait disturbance 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Non-cardiac chest pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Infections and infestations
    Catheter related infection 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 1/3 (33.3%) 0/9 (0%)
    Lung infection 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Periorbital infection 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Pharyngitis 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Sepsis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Skin infection 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Injury, poisoning and procedural complications
    Vascular access complication 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Investigations
    Activated partial thromboplastin time prolonged 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/13 (15.4%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Alanine aminotransferase increased 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Aspartate aminotransferase increased 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    GGT increased 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Lymphocyte count decreased 0/3 (0%) 2/3 (66.7%) 0/3 (0%) 4/13 (30.8%) 2/6 (33.3%) 2/3 (66.7%) 6/9 (66.7%)
    Lymphocyte count increased 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Neutrophil count decreased 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 8/13 (61.5%) 5/6 (83.3%) 3/3 (100%) 5/9 (55.6%)
    Platelet count decreased 0/3 (0%) 0/3 (0%) 0/3 (0%) 4/13 (30.8%) 3/6 (50%) 2/3 (66.7%) 5/9 (55.6%)
    Urine output decreased 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Weight loss 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    White blood cell decreased 0/3 (0%) 0/3 (0%) 0/3 (0%) 3/13 (23.1%) 2/6 (33.3%) 2/3 (66.7%) 5/9 (55.6%)
    Metabolism and nutrition disorders
    Anorexia 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 1/6 (16.7%) 1/3 (33.3%) 1/9 (11.1%)
    Hyperglycemia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Hyperkalemia 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Hypokalemia 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/13 (15.4%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Hyponatremia 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Hypophosphatemia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 1/9 (11.1%)
    Obesity 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 1/9 (11.1%)
    Musculoskeletal and connective tissue disorders
    Generalized muscle weakness 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Muscle weakness lower limb 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Muscle weakness right-sided 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, PROGRESSIVE DISEASE 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, PROGRESSIVE DISEASE 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Tumor pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Nervous system disorders
    Ataxia 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Dysarthria 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Dysphasia 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Headache 0/3 (0%) 1/3 (33.3%) 1/3 (33.3%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Hydrocephalus 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Hypersomnia 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Nervous system disorders - Other, HYPOTONIC 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Nervous system disorders - Other, PARALYSIS 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Oculomotor nerve disorder 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Peripheral motor neuropathy 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Peripheral sensory neuropathy 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Seizure 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/13 (15.4%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Psychiatric disorders
    Anxiety 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Insomnia 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Renal and urinary disorders
    Hematuria 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Reproductive system and breast disorders
    Irregular menstruation 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnea 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 1/9 (11.1%)
    Hypoxia 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 1/13 (7.7%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Pleural hemorrhage 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Respiratory, thoracic and mediastinal disorders - Other, VOCAL CORD PARALYSIS 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Stridor 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Skin and subcutaneous tissue disorders
    Hyperhidrosis 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Skin atrophy 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Skin ulceration 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Urticaria 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Vascular disorders
    Hypotension 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Other (Not Including Serious) Adverse Events
    400 mcg/m²/Dose BMN 673 QD+20mg/m²/Dose TEM,Max 800 mcg/Day 400 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 800 mcg/Day 600 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+40mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/doseBMN 673 BID+55mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM,Max 1000 mcg/Day
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/3 (100%) 3/3 (100%) 3/3 (100%) 13/13 (100%) 6/6 (100%) 3/3 (100%) 9/9 (100%)
    Blood and lymphatic system disorders
    Anemia 2/3 (66.7%) 2/3 (66.7%) 2/3 (66.7%) 12/13 (92.3%) 6/6 (100%) 3/3 (100%) 8/9 (88.9%)
    Cardiac disorders
    Cardiac disorders - Other, HEART MURMUR 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Cardiac disorders - Other, MURMUR LUSB 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Cardiac disorders - Other, NON RESTRICTIVE CARDIOMYOPATHY 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Pericardial effusion 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Sinus bradycardia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Sinus tachycardia 0/3 (0%) 1/3 (33.3%) 1/3 (33.3%) 5/13 (38.5%) 2/6 (33.3%) 3/3 (100%) 3/9 (33.3%)
    Ear and labyrinth disorders
    Ear and labyrinth disorders - Other, DECREASED HEARING 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Ear and labyrinth disorders - Other, HEARING LOSS 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Ear pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Hearing impaired 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/13 (15.4%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Tinnitus 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 1/6 (16.7%) 0/3 (0%) 1/9 (11.1%)
    Endocrine disorders
    Adrenal insufficiency 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Cushingoid 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 2/13 (15.4%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Endocrine disorders - Other, PANHYPOPITUITARISM 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Hypothyroidism 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 2/6 (33.3%) 0/3 (0%) 0/9 (0%)
    Precocious puberty 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Eye disorders
    Blurred vision 1/3 (33.3%) 0/3 (0%) 1/3 (33.3%) 2/13 (15.4%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Cataract 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Eye disorders - Other, DOUBLE VISION 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Eye disorders - Other, LEFT ORBITAL RECONSTRUCTION 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Eye disorders - Other, SPOTS IN VISUAL FIELD 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Eye disorders - Other, VISION IMPAIRMENT 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Photophobia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Gastrointestinal disorders
    Abdominal distension 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Abdominal pain 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 2/13 (15.4%) 2/6 (33.3%) 2/3 (66.7%) 2/9 (22.2%)
    Ascites 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Cheilitis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Constipation 1/3 (33.3%) 0/3 (0%) 1/3 (33.3%) 5/13 (38.5%) 4/6 (66.7%) 2/3 (66.7%) 4/9 (44.4%)
    Dental caries 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Diarrhea 1/3 (33.3%) 1/3 (33.3%) 1/3 (33.3%) 5/13 (38.5%) 2/6 (33.3%) 1/3 (33.3%) 3/9 (33.3%)
    Dyspepsia 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Dysphagia 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/13 (7.7%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Esophageal stenosis 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Fecal incontinence 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Flatulence 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Gastroesophageal reflux disease 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 2/13 (15.4%) 1/6 (16.7%) 0/3 (0%) 1/9 (11.1%)
    Gastrointestinal disorders - Other, GINGIVAL BLEEDING 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Gastrointestinal disorders - Other, OROPHARYNGEAL ERYTHEMA 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Gastrointestinal disorders - Other, VOMITING WITH BLOOD STREAKS 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Mucositis oral 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 1/6 (16.7%) 1/3 (33.3%) 0/9 (0%)
    Nausea 1/3 (33.3%) 1/3 (33.3%) 3/3 (100%) 6/13 (46.2%) 4/6 (66.7%) 2/3 (66.7%) 7/9 (77.8%)
    Oral pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Stomach pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/13 (15.4%) 1/6 (16.7%) 0/3 (0%) 1/9 (11.1%)
    Toothache 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 2/13 (15.4%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Vomiting 0/3 (0%) 1/3 (33.3%) 1/3 (33.3%) 5/13 (38.5%) 4/6 (66.7%) 3/3 (100%) 3/9 (33.3%)
    General disorders
    Chills 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 1/3 (33.3%) 0/9 (0%)
    Edema limbs 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 3/13 (23.1%) 3/6 (50%) 0/3 (0%) 1/9 (11.1%)
    Fatigue 3/3 (100%) 1/3 (33.3%) 0/3 (0%) 10/13 (76.9%) 5/6 (83.3%) 3/3 (100%) 6/9 (66.7%)
    Fever 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/13 (15.4%) 1/6 (16.7%) 1/3 (33.3%) 3/9 (33.3%)
    Gait disturbance 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 2/13 (15.4%) 1/6 (16.7%) 0/3 (0%) 1/9 (11.1%)
    Infusion related reaction 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Irritability 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 2/6 (33.3%) 0/3 (0%) 0/9 (0%)
    Malaise 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Non-cardiac chest pain 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 4/9 (44.4%)
    Pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/13 (15.4%) 2/6 (33.3%) 0/3 (0%) 3/9 (33.3%)
    Immune system disorders
    Allergic reaction 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Infections and infestations
    Infections and infestations - Other, HHV6 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Infections and infestations - Other, SHINGLES ZOSTER 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Infections and infestations - Other, THRUSH 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Infections and infestations - Other, URI 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Lip infection 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Mucosal infection 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 1/3 (33.3%) 1/9 (11.1%)
    Otitis media 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Papulopustular rash 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Paronychia 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Pharyngitis 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Skin infection 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 2/13 (15.4%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Upper respiratory infection 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Injury, poisoning and procedural complications
    Bruising 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 2/13 (15.4%) 1/6 (16.7%) 1/3 (33.3%) 0/9 (0%)
    Burn 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 1/13 (7.7%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Fall 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Injury, poisoning and procedural complications - Other, EAR CUT 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Injury, poisoning and procedural complications - Other, LEG LACERATION 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Injury, poisoning and procedural complications - Other, SCRATCHES 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Intraoperative neurological injury 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Vascular access complication 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Wound dehiscence 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Investigations
    Activated partial thromboplastin time prolonged 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Alanine aminotransferase increased 1/3 (33.3%) 1/3 (33.3%) 0/3 (0%) 3/13 (23.1%) 4/6 (66.7%) 1/3 (33.3%) 3/9 (33.3%)
    Alkaline phosphatase increased 1/3 (33.3%) 1/3 (33.3%) 1/3 (33.3%) 2/13 (15.4%) 1/6 (16.7%) 1/3 (33.3%) 7/9 (77.8%)
    Aspartate aminotransferase increased 1/3 (33.3%) 1/3 (33.3%) 1/3 (33.3%) 2/13 (15.4%) 2/6 (33.3%) 1/3 (33.3%) 5/9 (55.6%)
    Blood bilirubin increased 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/13 (15.4%) 1/6 (16.7%) 0/3 (0%) 3/9 (33.3%)
    Cholesterol high 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Creatinine increased 1/3 (33.3%) 0/3 (0%) 1/3 (33.3%) 4/13 (30.8%) 3/6 (50%) 2/3 (66.7%) 3/9 (33.3%)
    Hemoglobin increased 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Investigations - Other, ALK PHOS DECREASED 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Investigations - Other, ALT DECREASED 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Investigations - Other, ANION GAP INCREASED 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Investigations - Other, AST DECREASED 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Investigations - Other, BICARBONATE DECREASED 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Investigations - Other, BICARBONATE INCREASED 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Investigations - Other, BICARBONATE LOW 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Investigations - Other, BICARBONATE SERUM LOW 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Investigations - Other, BUN DECREASED 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Investigations - Other, CHLORIDE INCREASED 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Investigations - Other, ELEVATED BUN 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Investigations - Other, ELEVATED LDH 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Investigations - Other, HARD STOOL 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Investigations - Other, HCT INCREASED 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Investigations - Other, HIGH PLATELET COUNT 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Investigations - Other, HYPOCHLOREMIA 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Investigations - Other, INCREASED WBC L 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Investigations - Other, LOW BICARBONATE 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Investigations - Other, MONOCYTE COUNT INCREASED 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Investigations - Other, NEUTROPHIL COUNT INCREASED 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Investigations - Other, PLATELETS INCREASED 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Lymphocyte count decreased 1/3 (33.3%) 2/3 (66.7%) 2/3 (66.7%) 10/13 (76.9%) 4/6 (66.7%) 1/3 (33.3%) 4/9 (44.4%)
    Neutrophil count decreased 1/3 (33.3%) 2/3 (66.7%) 1/3 (33.3%) 7/13 (53.8%) 3/6 (50%) 0/3 (0%) 5/9 (55.6%)
    Platelet count decreased 2/3 (66.7%) 1/3 (33.3%) 1/3 (33.3%) 9/13 (69.2%) 4/6 (66.7%) 2/3 (66.7%) 5/9 (55.6%)
    Weight gain 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 2/6 (33.3%) 0/3 (0%) 0/9 (0%)
    Weight loss 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 2/13 (15.4%) 1/6 (16.7%) 2/3 (66.7%) 1/9 (11.1%)
    White blood cell decreased 1/3 (33.3%) 2/3 (66.7%) 2/3 (66.7%) 10/13 (76.9%) 5/6 (83.3%) 3/3 (100%) 7/9 (77.8%)
    Metabolism and nutrition disorders
    Anorexia 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 7/13 (53.8%) 1/6 (16.7%) 2/3 (66.7%) 3/9 (33.3%)
    Dehydration 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Hypercalcemia 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 2/9 (22.2%)
    Hyperglycemia 2/3 (66.7%) 1/3 (33.3%) 2/3 (66.7%) 5/13 (38.5%) 2/6 (33.3%) 0/3 (0%) 3/9 (33.3%)
    Hypermagnesemia 1/3 (33.3%) 1/3 (33.3%) 0/3 (0%) 3/13 (23.1%) 0/6 (0%) 0/3 (0%) 5/9 (55.6%)
    Hypernatremia 0/3 (0%) 2/3 (66.7%) 0/3 (0%) 2/13 (15.4%) 0/6 (0%) 0/3 (0%) 2/9 (22.2%)
    Hypoalbuminemia 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 5/13 (38.5%) 3/6 (50%) 2/3 (66.7%) 4/9 (44.4%)
    Hypocalcemia 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 2/13 (15.4%) 1/6 (16.7%) 2/3 (66.7%) 3/9 (33.3%)
    Hypoglycemia 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 2/13 (15.4%) 1/6 (16.7%) 1/3 (33.3%) 0/9 (0%)
    Hypokalemia 1/3 (33.3%) 0/3 (0%) 1/3 (33.3%) 2/13 (15.4%) 0/6 (0%) 2/3 (66.7%) 2/9 (22.2%)
    Hypomagnesemia 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/13 (0%) 0/6 (0%) 1/3 (33.3%) 1/9 (11.1%)
    Hyponatremia 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 1/6 (16.7%) 2/3 (66.7%) 4/9 (44.4%)
    Hypophosphatemia 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 4/13 (30.8%) 2/6 (33.3%) 0/3 (0%) 2/9 (22.2%)
    Metabolism and nutrition disorders - Other, CHLORIDE LEVEL 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Obesity 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Avascular necrosis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Back pain 2/3 (66.7%) 0/3 (0%) 0/3 (0%) 3/13 (23.1%) 3/6 (50%) 2/3 (66.7%) 3/9 (33.3%)
    Bone pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Buttock pain 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Chest wall pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Flank pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Generalized muscle weakness 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/13 (7.7%) 2/6 (33.3%) 0/3 (0%) 0/9 (0%)
    Joint range of motion decreased 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Kyphosis 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Muscle weakness left-sided 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Muscle weakness lower limb 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Muscle weakness right-sided 0/3 (0%) 0/3 (0%) 0/3 (0%) 3/13 (23.1%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Muscle weakness trunk 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Muscle weakness upper limb 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 1/6 (16.7%) 1/3 (33.3%) 0/9 (0%)
    Musculoskeletal and connective tissue disorder - Other, L WRIST CONTRACTURE 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Musculoskeletal and connective tissue disorder - Other, LARGE OCCIPITAL SKULL DEFECT 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Musculoskeletal and connective tissue disorder - Other, LEG CRAMPS 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Musculoskeletal and connective tissue disorder - Other, LEG SPASMS 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Myalgia 0/3 (0%) 1/3 (33.3%) 1/3 (33.3%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Neck pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/13 (15.4%) 1/6 (16.7%) 0/3 (0%) 2/9 (22.2%)
    Pain in extremity 1/3 (33.3%) 0/3 (0%) 1/3 (33.3%) 3/13 (23.1%) 3/6 (50%) 2/3 (66.7%) 5/9 (55.6%)
    Scoliosis 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumor pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/13 (15.4%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Nervous system disorders
    Abducens nerve disorder 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 2/13 (15.4%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Ataxia 0/3 (0%) 1/3 (33.3%) 1/3 (33.3%) 3/13 (23.1%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Brachial plexopathy 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Cognitive disturbance 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Concentration impairment 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Depressed level of consciousness 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Dizziness 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/13 (0%) 1/6 (16.7%) 1/3 (33.3%) 3/9 (33.3%)
    Dysarthria 0/3 (0%) 1/3 (33.3%) 1/3 (33.3%) 1/13 (7.7%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Dysgeusia 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Dysphasia 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Encephalopathy 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Facial nerve disorder 0/3 (0%) 1/3 (33.3%) 1/3 (33.3%) 5/13 (38.5%) 1/6 (16.7%) 1/3 (33.3%) 0/9 (0%)
    Glossopharyngeal nerve disorder 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Headache 3/3 (100%) 1/3 (33.3%) 1/3 (33.3%) 3/13 (23.1%) 0/6 (0%) 3/3 (100%) 5/9 (55.6%)
    Hydrocephalus 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Hypoglossal nerve disorder 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    IVth nerve disorder 0/3 (0%) 1/3 (33.3%) 1/3 (33.3%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Lethargy 0/3 (0%) 1/3 (33.3%) 1/3 (33.3%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Memory impairment 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Nervous system disorders - Other, DIFFICULTIES WITH BALANCE 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Nervous system disorders - Other, LEFT HEMIPLEGIA 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Neuralgia 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Nystagmus 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Oculomotor nerve disorder 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/13 (15.4%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Paresthesia 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Peripheral motor neuropathy 1/3 (33.3%) 0/3 (0%) 1/3 (33.3%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Peripheral sensory neuropathy 1/3 (33.3%) 0/3 (0%) 1/3 (33.3%) 2/13 (15.4%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Presyncope 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Pyramidal tract syndrome 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Recurrent laryngeal nerve palsy 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Seizure 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Somnolence 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Spasticity 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Tremor 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Psychiatric disorders
    Agitation 0/3 (0%) 1/3 (33.3%) 1/3 (33.3%) 1/13 (7.7%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Anxiety 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 4/13 (30.8%) 1/6 (16.7%) 0/3 (0%) 1/9 (11.1%)
    Confusion 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 2/6 (33.3%) 0/3 (0%) 0/9 (0%)
    Delirium 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Depression 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/13 (15.4%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Hallucinations 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Insomnia 1/3 (33.3%) 1/3 (33.3%) 1/3 (33.3%) 0/13 (0%) 2/6 (33.3%) 0/3 (0%) 1/9 (11.1%)
    Psychiatric disorders - Other, HX OF ADHD 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Restlessness 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Renal and urinary disorders
    Cystitis noninfective 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Hematuria 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 1/3 (33.3%) 0/9 (0%)
    Hemoglobinuria 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Proteinuria 0/3 (0%) 1/3 (33.3%) 1/3 (33.3%) 1/13 (7.7%) 1/6 (16.7%) 0/3 (0%) 3/9 (33.3%)
    Renal and urinary disorders - Other, BLADDER PAIN 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Renal and urinary disorders - Other, GLUCOSE IN URINE 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Urinary frequency 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Urinary incontinence 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 2/13 (15.4%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Urinary retention 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 1/3 (33.3%) 1/9 (11.1%)
    Urinary tract obstruction 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Urinary tract pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Urinary urgency 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Urine discoloration 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Reproductive system and breast disorders
    Penile pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Respiratory, thoracic and mediastinal disorders
    Allergic rhinitis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 2/6 (33.3%) 0/3 (0%) 0/9 (0%)
    Atelectasis 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/13 (15.4%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Cough 1/3 (33.3%) 0/3 (0%) 2/3 (66.7%) 3/13 (23.1%) 3/6 (50%) 1/3 (33.3%) 2/9 (22.2%)
    Dyspnea 0/3 (0%) 0/3 (0%) 0/3 (0%) 3/13 (23.1%) 0/6 (0%) 0/3 (0%) 2/9 (22.2%)
    Epistaxis 0/3 (0%) 0/3 (0%) 0/3 (0%) 3/13 (23.1%) 1/6 (16.7%) 0/3 (0%) 1/9 (11.1%)
    Hiccups 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Hypoxia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 2/9 (22.2%)
    Nasal congestion 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 2/6 (33.3%) 0/3 (0%) 2/9 (22.2%)
    Pleural effusion 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/13 (15.4%) 1/6 (16.7%) 0/3 (0%) 1/9 (11.1%)
    Productive cough 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Respiratory, thoracic and mediastinal disorders - Other, ASTHMA 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 1/6 (16.7%) 0/3 (0%) 1/9 (11.1%)
    Respiratory, thoracic and mediastinal disorders - Other, OBSTRUCTIVE SLEEP APNEA 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Respiratory, thoracic and mediastinal disorders - Other, REQUIRES TRACH WITH FLOW OVERNIGHT 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Respiratory, thoracic and mediastinal disorders - Other, RETRACTIONS 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Respiratory, thoracic and mediastinal disorders - Other, RHINORRHEA 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Respiratory, thoracic and mediastinal disorders - Other, SHORTNESS OF BREATH 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Respiratory, thoracic and mediastinal disorders - Other, TACHYPNEA 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Respiratory, thoracic and mediastinal disorders - Other, WHEEZING 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Sore throat 0/3 (0%) 0/3 (0%) 2/3 (66.7%) 2/13 (15.4%) 1/6 (16.7%) 1/3 (33.3%) 0/9 (0%)
    Skin and subcutaneous tissue disorders
    Alopecia 1/3 (33.3%) 1/3 (33.3%) 1/3 (33.3%) 6/13 (46.2%) 2/6 (33.3%) 1/3 (33.3%) 3/9 (33.3%)
    Dry skin 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 2/13 (15.4%) 2/6 (33.3%) 0/3 (0%) 0/9 (0%)
    Hirsutism 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Hyperhidrosis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Pain of skin 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Periorbital edema 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Pruritus 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Rash acneiform 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Rash maculo-papular 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Skin and subcutaneous tissue disorders - Other, ABRASION ON LEG 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Skin and subcutaneous tissue disorders - Other, ERYTHEMA 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Skin and subcutaneous tissue disorders - Other, LEFT LOWER LEG ERYTHEMA 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Skin and subcutaneous tissue disorders - Other, MOM NOTICED DARK VEINS ON BACK 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Skin and subcutaneous tissue disorders - Other, PEELING LEFT HEEL 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Skin and subcutaneous tissue disorders - Other, PEELING SKIN ON HEEL AREA 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 1/3 (33.3%) 0/9 (0%)
    Skin and subcutaneous tissue disorders - Other, PEELING SKIN, FINGERTIPS 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Skin and subcutaneous tissue disorders - Other, POISON IVY RASH 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Skin and subcutaneous tissue disorders - Other, RASH 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Skin and subcutaneous tissue disorders - Other, RED HANDS AND CHEEKS 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Skin and subcutaneous tissue disorders - Other, RIGHT UPPER HEAD AND RIGHT POSTERIOR HEAD LESION 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Skin and subcutaneous tissue disorders - Other, SKIN LESIONS 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Skin and subcutaneous tissue disorders - Other, TENDERNESS OVER SPINE 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 0/9 (0%)
    Skin hyperpigmentation 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 1/6 (16.7%) 0/3 (0%) 1/9 (11.1%)
    Skin hypopigmentation 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Skin ulceration 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 0/6 (0%) 0/3 (0%) 1/9 (11.1%)
    Vascular disorders
    Hypertension 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 2/6 (33.3%) 2/3 (66.7%) 1/9 (11.1%)
    Hypotension 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/13 (15.4%) 0/6 (0%) 0/3 (0%) 2/9 (22.2%)
    Lymphedema 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/13 (7.7%) 0/6 (0%) 0/3 (0%) 0/9 (0%)
    Thromboembolic event 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 1/6 (16.7%) 0/3 (0%) 1/9 (11.1%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Results Reporting Coordinator
    Organization Children's Oncology Group
    Phone 626-447-0064
    Email resultsreportingcoordinator@childrensoncologygroup.org
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT02116777
    Other Study ID Numbers:
    • NCI-2014-00804
    • NCI-2014-00804
    • ADVL1411
    • ADVL1411
    • UM1CA097452
    First Posted:
    Apr 17, 2014
    Last Update Posted:
    Mar 26, 2021
    Last Verified:
    Mar 1, 2021