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Completed

NCT Number: NCT01449370

Dose Escalation Study of TAK-117 (MLN1117) in Subjects With Advanced Cancer

The purpose of this study is to determine the maximum tolerated dose (MTD) and/or optimal biologic dose(OBD), safety and tolerability, dose-limiting toxicity (DLT) of TAK-117 when administered orally in subjects with advanced solid malignancies.

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Key information

Conditions

Metastatic Solid Tumors Congenital Abnormalities Congenital, Hereditary, and Neonatal Diseases and Abnormalities Genetic Diseases, Inborn Hereditary Sensory and Autonomic Neuropathies Heredodegenerative Disorders, Nervous System Neoplasms Nervous System Diseases Nervous System Malformations Neurodegenerative Diseases Neuromuscular Diseases Peripheral Nervous System Diseases Polyneuropathies

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Barcelona, Spain

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Subjects have had their PIK3CA gene mutation status assessed prior to enrolling into the study
  • Subjects must have documented disease progression prior to enrolling into the study
  • locally advanced or metastatic solid tumors with the exception of primary brain tumor, and have failed or are not eligible for standard of care therapy.
  • Age greater than or equal to (>=) 18 years, including males and females;
  • Eastern cooperative oncology group (ECOG) performance status (PS) 0-1;
  • Adequate organ function;
  • Male subjects must be surgically sterile or must agree to use physician-approved contraception during the study and for 30 days following the last study drug administration;
  • Ability to swallow oral medications;
  • Ability to understand and willingness to sign informed consent prior to initiation of any study procedures;
  • For women of child-bearing potential, negative serum pregnancy test within 14 days prior to the first study drug administration and use of physician-approved method of birth control from 30 days prior to the first study drug administration to 30 days following the last study drug administration

Exclusion criteria

  • Diagnosis of primary brain tumor; untreated brain metastasis or history of leptomeningeal disease or spinal cord compression;
  • Received prior cancer or other investigational therapy within 2 weeks prior to the first administration of study drug;
  • Have received a systemic corticosteroid within one week prior to the first administration of study drug;
  • Clinically significant cardiac disease;
  • Myocardial infarction or unstable angina within 6 months prior to the first administration of study drug;
  • Malabsorption ;
  • Poorly controlled diabetes mellitus;
  • Pregnancy (positive serum or urine pregnancy test) or breast feeding;
  • Untreated brain metastasis or history of leptomeningeal disease or spinal cord compression;
  • Failed to recover from the reversible effects of prior anticancer therapies;
  • Have received a selective phosphoinositide-3-kinase alpha isoform (PI3K-alpha) inhibitor
  • Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central nervous system (CNS) disease, active infection, or any other condition that could compromise the subject's participation in the study
  • Known human immunodeficiency virus (HIV) infection
  • Have a secondary malignancy within the last 3 years prior to first dose of study drug, excluding treated non-melanoma skin cancer, carcinoma in situ, or locally-treated prostate cancer

Treatment and study plan

TAK-117

Drug

oral administration of TAK-117, daily and intermittent schedules.

Primary outcomes

  1. Maximum Tolerated Dose (MTD) of TAK-117

    Time frame: Baseline up to Cycle 1 Day 21

    MTD is highest dose level of TAK-117 at which no more than 1 out of 6 participants had a dose limiting toxicity (DLT) during first cycle. DLT was any 1 of following events occurring within first 21 days of Cycle 1 of TAK-117 administration, Grade 2: fasting hyperglycemia for >14 days. Grade 3: nausea and/or vomiting/diarrhea for >7 days; rash for >7 days; thrombocytopenia with bleeding; fasting hyperglycemia for >24 hours(hr). Grade >=3:nonhematologic toxicity considered clinically significant by investigator. Grade 4:neutropenia (absolute neutrophil count <=0.5*10^9per liter[/L]) for >7 days in absence of growth factor support; neutropenia of any duration accompanied with fever >=38.5 degree Celsius and/or systemic infection. Grade >=4:hematologic toxicity. Inability to administer at least 75% of planned doses of TAK-117 within Cycle 1 due to its related toxicity;Any clinically significant occurrence that investigators and sponsor agreed would place participants at undue safety risk.

  2. Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Death, Adverse Events (AEs) Leading to Discontinuation of Study Drug, and DLTs in Cycle 1

    Time frame: Baseline up to Cycle 27 Day 45

  3. Number of Participants With Highest Level of TEAEs Severity

    Time frame: Baseline up to Cycle 27 Day 45

    Severity of AEs was evaluated based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0 as follow: Grade 1 (mild); Grade 2 (moderate); Grade 3 (severe); Grade 4 (life-threatening); Grade 5 (fatal).

  4. Number of Participants With Clinically Meaningful Changes in Laboratory Values

    Time frame: Baseline up to Cycle 27 Day 45

  5. Number of Participants With Clinically Meaningful Changes in Vital Signs

    Time frame: Baseline up to Cycle 27 day 45

  6. Number of Participants With Clinically Meaningful Changes in Electrocardiogram (ECG)

    Time frame: Baseline up to Cycle 27 Day 45

Secondary outcomes

  1. Overall Response Rate (ORR)

    Time frame: Cycle 1 Day 8 up to Cycle 27 Day 1 or disease progression or death

    The estimate of the ORR is calculated as crude percentage of participants who's best overall response is complete response (CR) or partial response (PR). Objective response (CR and PR) as determined by the participants best tumor response was assessed using response evaluation criteria in solid tumors (RECIST) version 1.1. As per RECIST version 1.1, CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis <10 millimeter [mm]). No new lesions. PR was defined as >=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. Stable disease was defined as not qualifying for CR, PR, and progressive disease (PD).

  2. Duration of Objective Response

    Time frame: Cycle 1 Day 8 up to Cycle 27 Day 1 or disease progression or death

    Duration of response was to be calculated for participants who achieved CR or PR. Duration of objective response was defined as the number of days from the start date of PR or CR (whichever response was achieved first) to the first date that PD or disease progression was objectively documented. The duration of objective response was to be right-censored for participants who achieved CR or PR and met 1 of the following conditions: Non-protocol anticancer treatment started before documentation of PD; Documented PD after more than 1 missed disease assessment visit; Alive and did not have documentation of PD before a data analysis cutoff date.

  3. Clinical Benefit Rate (CBR)

    Time frame: Cycle 1 Day 8 up to Cycle 27 Day 1 or disease progression or death

    Clinical benefit rate was defined as the participants who achieved stable disease (SD) for at least 15 weeks, CR, or PR. The estimate of the CBR was calculated as crude percentage of participants whose best ORR was CR, PR or SD for at least 90 days.

  4. Cmax: Maximum Observed Plasma Concentration for TAK-117

    Time frame: Process A: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 24 hrs) post-dose; Process B: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 48 hrs) post-dose

  5. Ctrough: Observed Concentration at the End of Dosing Interval for TAK-117

    Time frame: Process A: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 24 hrs) post-dose; Process B: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 48 hrs) post-dose

  6. Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-117

    Time frame: Process A: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 24 hrs) post-dose; Process B: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 48 hrs) post-dose

  7. T 1/2z: Terminal Disposition Phase Half-life for TAK-117

    Time frame: Process A: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 24 hrs) post-dose; Process B: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 48 hrs) post-dose

  8. AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-117

    Time frame: Process A: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 24 hrs) post-dose; Process B: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 48 hrs) post-dose

  9. AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-117

    Time frame: Process A: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 24 hrs) post-dose; Process B: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 48 hrs) post-dose

  10. %AUC Extrapolated: Percentage of Area Under Concentration-extrapolated

    Time frame: Process A: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 24 hrs) post-dose; Process B: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 48 hrs) post-dose

  11. Percent Change From Baseline in Pharmacodynamic Markers

    Time frame: Cycle 1 Day 8

    Pharmacodynamic markers included phosphorylated ribosomal protein S6 (PS6), phosphorylated eukaryotic initiation factor 4E-binding protein 1 (P4EBP1), phosphorylated N-myc downstream regulated gene 1 (PNDRG1), phosphorylated proline-rich AKT substrate of 40 kilodaltons (PPRAS40), and phosphorylated serine/threonine protein kinase AKT (PAKT). Analysis population (n) for each skin biopsy biomarker is as follow: P4EBP1 (n=6,6,6,2,2,0,0,0,0,1,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0); PAKT and PNDRG1 (n=6,6,7,2,2,0,0,0,0,1,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0); PPRAS40 (n= 6,0,6,2,2,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0); PS6 (n=6,6,7,2,2,0,0,0,0,1,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0)."n" for each tumor tissue biomarkers is as follow: P4EBP1, PAKT, PNDRG1, and PS6 (n=1,1,0,0,1,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0); PPRAS40 (n= 1,0,0,0,1,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0).

Sponsors and collaborators

Lead sponsor

Millennium Pharmaceuticals, Inc.

Industry

Registry information

Official study title

A Phase I, Dose Escalation Study of MLN1117 in Subjects With Advanced Solid Malignancies Followed by Expansion in Subjects With Measurable Disease

Important dates

Study start
2011
Primary completion
2015
Study completion
2016
First posted
Oct 10, 2011
Registry last updated
Mar 9, 2017

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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