Dose Escalation Study of MLN0128 in Participants With Advanced Malignancies
18 mars 2020 mis à jour par: Millennium Pharmaceuticals, Inc.
A Phase I, Open Label, Dose Escalation Study of Oral Administration of Single Agent INK128 in Subjects With Advanced Malignancies Followed by an Expansion in Subjects With Measurable Disease
This is a Phase I, open label, Dose Escalation study of oral administration of single agent MLN0128 in participants with Advanced Malignancies followed by an Expansion Phase in participants with renal cell carcinoma, endometrial cancer or urothelial cancer who have measurable disease.
Aperçu de l'étude
Statut
Complété
Les conditions
Intervention / Traitement
Description détaillée
The drug being tested in this study is called MLN0128. MLN0128 is being tested to treat people who have Advanced Malignancies.
The study enrolled approximately 198 patients. Participants were assigned to one of the following dose regimens in the Dose Escalation Phase to establish the Maximum Tolerated Dose (MTD):
- MLN0128 QD
- MLN0128 QW
- MLN0128 QDx3dQW
- MLN0128 QDx5dQW
MLN0128 capsule, orally, once daily (QD) or Once weekly (QW) in the Dose Escalation Phase until MTD was established.
Once MTD was determined, participants were then enrolled in the Dose Expansion Phase to receive:
- MLN0128 5 mg QD
- MLN0128 30 mg QW
- MLN0128 40 mg QW
This multi-centre trial was conducted worldwide. The overall time to participate in this study was approximately 244 weeks. Participants will make multiple visits to the clinic, and were contacted by telephone OR plus a final visit after last dose of study drug for a follow-up assessment.
Type d'étude
Interventionnel
Inscription (Réel)
198
Phase
- La phase 1
Contacts et emplacements
Cette section fournit les coordonnées de ceux qui mènent l'étude et des informations sur le lieu où cette étude est menée.
Lieux d'étude
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Barcelona, Espagne
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Valencia, Espagne
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Arizona
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Scottsdale, Arizona, États-Unis
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California
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Los Angeles, California, États-Unis
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Florida
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Miami, Florida, États-Unis
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Sarasota, Florida, États-Unis
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Indiana
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Indianapolis, Indiana, États-Unis
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Massachusetts
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Boston, Massachusetts, États-Unis
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Michigan
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Ann Arbor, Michigan, États-Unis
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Detroit, Michigan, États-Unis
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New York
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Buffalo, New York, États-Unis
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New York, New York, États-Unis
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Ohio
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Cleveland, Ohio, États-Unis
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Oklahoma
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Oklahoma City, Oklahoma, États-Unis
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Pennsylvania
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Philadelphia, Pennsylvania, États-Unis
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Tennessee
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Nashville, Tennessee, États-Unis
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Critères de participation
Les chercheurs recherchent des personnes qui correspondent à une certaine description, appelée critères d'éligibilité. Certains exemples de ces critères sont l'état de santé général d'une personne ou des traitements antérieurs.
Critère d'éligibilité
Âges éligibles pour étudier
18 ans et plus (Adulte, Adulte plus âgé)
Accepte les volontaires sains
Non
Sexes éligibles pour l'étude
Tout
La description
Inclusion Criteria:
- Voluntary written consent
- Locally advanced or metastatic solid tumors with the exception of primary brain tumor, and have failed standard of care therapy
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Ability to swallow oral medications
- For women of child-bearing potential, negative serum or urine 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 90 days following the last study drug administration
- Male participants must be surgically sterile or must agree to use physician-approved contraception during the study and for 90 days following the last study drug administration
- Clinical laboratory values as specified in the protocol
Additionally, to be eligible for the Dose Expansion portion of the study:
- Participants must have evidence of measurable disease per response evaluation criteria in solid tumors (RECIST) version 1.1 by radiographic techniques or magnetic resonance imaging
- Participants must have a pathologic diagnosis of advanced or recurrent endometrial adenocarcinoma and must have failed at least 1 prior line of standard chemotherapy
- Participants must have a pathologic diagnosis of advanced/metastatic urothelial cancer (carcinoma of the bladder, ureter, and/or renal pelvis) and must have failed at least 1 line of prior therapy in the metastatic/unresectable setting
- Participants must have a pathologic diagnosis of advanced renal cell carcinoma (RCC), with histological or cytological confirmation of RCC and must have failed at least 1 prior line of anti-vascular endothelial growth factor therapy (VEGF) therapy (including but not limited to sunitinib, and/or sorafenib, and/or bevacizumab and/or pazopanib, and/or axitinib) and must not have received prior therapy with a target of rapamycin complex 1 (TORC1) inhibitor (such as temsirolimus or everolimus); or
- Participants must have a pathologic diagnosis of advanced renal cell carcinoma (RCC) and must have progressed on treatment with a TORC1 inhibitor (such as temsirolimus or everolimus).
Exclusion Criteria:
- Diagnosis of primary brain tumor
- Have received prior cancer or other investigational therapy within 2 weeks prior to the first administration of study drug
- Known impaired cardiac function or clinically significant cardiac disease
- Known treatment with systemic corticosteroid within one week prior to the first administration of study drug
- Diabetes mellitus
- Human immunodeficiency virus (HIV) infection
- Known active cardiovascular disease condition as specified in protocol
- Failed to recover from the reversible effects of prior anticancer therapies
- Pregnancy (positive serum or urine pregnancy test) or breast feeding
- Malabsorption due to prior gastrointestinal (GI) surgery, GI disease
- Other clinically significant co-morbidities
Please note that there are additional inclusion and exclusion criteria. The study center will determine if you meet all of the criteria.
Site personnel will explain the trial in detail and answer any question you may have if you do qualify for the study. You can then decide whether or not you wish to participate. If you do not qualify for the trial, site personnel will explain the reasons.
Plan d'étude
Cette section fournit des détails sur le plan d'étude, y compris la façon dont l'étude est conçue et ce que l'étude mesure.
Comment l'étude est-elle conçue ?
Détails de conception
- Objectif principal: Traitement
- Répartition: Non randomisé
- Modèle interventionnel: Affectation séquentielle
- Masquage: Aucun (étiquette ouverte)
Armes et Interventions
Groupe de participants / Bras |
Intervention / Traitement |
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Expérimental: MLN0128 QD
MLN0128 2 mg, 4 mg, 6 mg or 7 mg, capsule, orally, once daily (QD) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 52.1 weeks).
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MLN0128 capsules
Autres noms:
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Expérimental: MLN0128 QW
MLN0128 7 mg, 10 mg, 15 mg, 20 mg, 30 mg or 40 mg capsule, orally, once weekly (QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 139.4 weeks).
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MLN0128 capsules
Autres noms:
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Expérimental: MLN0128 QDx3d QW
MLN0128 6 mg, 9 mg, 12 mg, 16 mg or 20 mg capsule, orally, once daily every 3 days a week (QDx3d QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 129.4 weeks).
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MLN0128 capsules
Autres noms:
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Expérimental: MLN0128 QDx5d QW
MLN0128 7 mg, 10 mg or 13 mg capsule, orally, once daily every 5 days a week (QDx5d QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 161.9 weeks).
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MLN0128 capsules
Autres noms:
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Expérimental: MLN0128 5 mg QD
MLN0128 5 mg, capsule, orally, QD in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 98.3 weeks).
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MLN0128 capsules
Autres noms:
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Expérimental: MLN0128 30 mg QW
MLN0128 30 mg, capsule, orally QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 240 weeks).
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MLN0128 capsules
Autres noms:
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Expérimental: MLN0128 40 mg QW
MLN0128 40 mg, capsule, orally, QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 100.1 weeks).
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MLN0128 capsules
Autres noms:
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Que mesure l'étude ?
Principaux critères de jugement
Mesure des résultats |
Description de la mesure |
Délai |
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Dose Escalation Phase: Maximum Tolerated Dose (MTD)
Délai: Cycle 1 (28 Days)
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MTD was defined as the highest dose level of MLN0128 at which no more than 1 out of 6 evaluable participants experienced a DLT during the first cycle (28 days) of therapy.
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Cycle 1 (28 Days)
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Dose Escalation Phase: Number of Participants With Dose Limiting Toxicities (DLTs)
Délai: Cycle 1 (28 days)
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DLTs were defined as MLN0128-related treatment-emergent adverse events (TEAEs) that occurred within the Cycle 1 (first 28 days of treatment) as per Common Terminology Criteria for Adverse Events (CTCAE): Any ≥Grade 3 or non-hematologic toxicity except for Grade 3 nausea and/or vomiting and diarrhea, Grade 3 hyperglycemia lasting ≤ 14 days, Grade 3 rash lasting ≤ 3 days; Grade 4 neutropenia lasting >7 days in the absence of growth factor support; Grade 4 neutropenia of any duration associated with fever ≥38.5 degree celsius and/or systemic infection; Any other Grade 4 hematologic toxicity; Inability to administer at least 75% of planned doses of MLN0128 within Cycle 1 due to drug-related toxicity and any clinically significant occurrence that the investigators and sponsor agreed would place participants at an undue safety risk.
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Cycle 1 (28 days)
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Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug
Délai: First dose of study drug through 30 days after the administration of the last dose of study drug (Up to approximately 244 weeks)
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An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment.
A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
A serious adverse event is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.
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First dose of study drug through 30 days after the administration of the last dose of study drug (Up to approximately 244 weeks)
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Dose Expansion: Objective Response Rate (ORR)
Délai: From the first dose of study drug up to disease progression or death (Up to approximately 240 weeks)
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ORR is defined as the percentage of participants who achieved complete response (CR) or partial response (PR based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
CR is defined as disappearance of all target lesions and PR was defined of at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD and for non-target lesions.
Data was categorized as per type of cancer.
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From the first dose of study drug up to disease progression or death (Up to approximately 240 weeks)
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Dose Expansion Phase: Duration of Objective Response
Délai: From the first dose of study drug up to disease progression or death (Up to approximately 240 weeks)
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Duration of objective response is defined as the number of months from the start date of CR or PR (whichever occurred first) based on RECIST Criteria version 1.1 to the first date of objectively documented progressive disease (PD) for participants who achieved CR or PR.
PD is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).
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From the first dose of study drug up to disease progression or death (Up to approximately 240 weeks)
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Dose Expansion: Duration of Stable Disease (SD)
Délai: From the first dose of study drug up to disease progression or death (Up to approximately 240 weeks)
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Duration of SD was evaluated for participants with best response of SD and is defined as number of months from date of first dose to date of PD.
As per RECIST 1.1, SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
PR was defined of at least a 30% decrease in sum of longest diameter (LD) of target lesions, taking as reference the baseline sum LD and for non-target lesions.
PD is defined as at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (this includes baseline sum if that is smallest on study).
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From the first dose of study drug up to disease progression or death (Up to approximately 240 weeks)
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Mesures de résultats secondaires
Mesure des résultats |
Description de la mesure |
Délai |
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Cmax: Maximum Observed Plasma Concentration for MLN0128
Délai: Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
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Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
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Ctrough: Observed Concentration at the End of a Dosing Interval
Délai: Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
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Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
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Terminal Phase Elimination Half-life (T1/2) for MLN0128
Délai: Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
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Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
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AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128
Délai: Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
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Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
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AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN0128
Délai: Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
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Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
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Tmax: Time to Maximum Observed Plasma Concentration for MLN0128
Délai: Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
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Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
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Percentage Area Under Plasma Concentration Time Curve Extrapolated
Délai: Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
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Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
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Percentage Change From Baseline in Eukaryotic Initiation Factor 4E-binding Protein 1 (P4EBP1), Serine/Threonine Protein Kinase B (PAKT) and Ribosomal Protein S6 (PS6)
Délai: Baseline, Cycle 1 Week 2
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P4EBP, PAKT and PS6 were assayed in skin biopsies.
A negative percentage change from Baseline indicates improvement.
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Baseline, Cycle 1 Week 2
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Collaborateurs et enquêteurs
C'est ici que vous trouverez les personnes et les organisations impliquées dans cette étude.
Parrainer
Publications et liens utiles
La personne responsable de la saisie des informations sur l'étude fournit volontairement ces publications. Il peut s'agir de tout ce qui concerne l'étude.
Dates d'enregistrement des études
Ces dates suivent la progression des dossiers d'étude et des soumissions de résultats sommaires à ClinicalTrials.gov. Les dossiers d'étude et les résultats rapportés sont examinés par la Bibliothèque nationale de médecine (NLM) pour s'assurer qu'ils répondent à des normes de contrôle de qualité spécifiques avant d'être publiés sur le site Web public.
Dates principales de l'étude
Début de l'étude (Réel)
4 janvier 2010
Achèvement primaire (Réel)
7 février 2019
Achèvement de l'étude (Réel)
7 février 2019
Dates d'inscription aux études
Première soumission
27 janvier 2010
Première soumission répondant aux critères de contrôle qualité
27 janvier 2010
Première publication (Estimation)
29 janvier 2010
Mises à jour des dossiers d'étude
Dernière mise à jour publiée (Réel)
1 avril 2020
Dernière mise à jour soumise répondant aux critères de contrôle qualité
18 mars 2020
Dernière vérification
1 mars 2020
Plus d'information
Termes liés à cette étude
Termes MeSH pertinents supplémentaires
Autres numéros d'identification d'étude
- INK128-001
- 2009-017284-42 (Numéro EudraCT)
- U1111-1187-4258 (Autre identifiant: World Health Organization)
Plan pour les données individuelles des participants (IPD)
Prévoyez-vous de partager les données individuelles des participants (DPI) ?
OUI
Description du régime IPD
Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com
for details).
To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias.
Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.
Informations sur les médicaments et les dispositifs, documents d'étude
Étudie un produit pharmaceutique réglementé par la FDA américaine
Oui
Étudie un produit d'appareil réglementé par la FDA américaine
Non
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