Clinical trial NCT01058707: Dose Escalation Study of MLN0128 in Participants With Advanced Malignancies
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced Solid Malignancies
Keywords: Solid tumors, MLN0128, TORC1/2 inhibitors
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2010-01-29
Enrollment: 198
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: The Escalation Phase was sequential and the Expansion Phase was parallel.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Dose Escalation Phase: Maximum Tolerated Dose (MTD)
timeFrame: Cycle 1 (28 Days)
measure: Dose Escalation Phase: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Cycle 1 (28 days)
measure: 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
timeFrame: First dose of study drug through 30 days after the administration of the last dose of study drug (Up to approximately 244 weeks)
measure: Dose Expansion: Objective Response Rate (ORR)
timeFrame: From the first dose of study drug up to disease progression or death (Up to approximately 240 weeks)
measure: Dose Expansion Phase: Duration of Objective Response
timeFrame: From the first dose of study drug up to disease progression or death (Up to approximately 240 weeks)
measure: Dose Expansion: Duration of Stable Disease (SD)
timeFrame: From the first dose of study drug up to disease progression or death (Up to approximately 240 weeks)
Secondary outcomes:
measure: Cmax: Maximum Observed Plasma Concentration for MLN0128
timeFrame: Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
measure: Ctrough: Observed Concentration at the End of a Dosing Interval
timeFrame: Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
measure: Terminal Phase Elimination Half-life (T1/2) for MLN0128
timeFrame: Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
measure: AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128
timeFrame: Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
measure: AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN0128
timeFrame: Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
measure: Tmax: Time to Maximum Observed Plasma Concentration for MLN0128
timeFrame: Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
measure: Percentage Area Under Plasma Concentration Time Curve Extrapolated
timeFrame: Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
measure: Percentage Change From Baseline in Eukaryotic Initiation Factor 4E-binding Protein 1 (P4EBP1), Serine/Threonine Protein Kinase B (PAKT) and Ribosomal Protein S6 (PS6)
timeFrame: Baseline, Cycle 1 Week 2
Other outcomes:
Locations:
city: Scottsdale
country: United States
state: Arizona
city: Los Angeles
country: United States
state: California
city: Miami
country: United States
state: Florida
city: Sarasota
country: United States
state: Florida
city: Indianapolis
country: United States
state: Indiana
city: Boston
country: United States
state: Massachusetts
city: Ann Arbor
country: United States
state: Michigan
city: Detroit
country: United States
state: Michigan
city: Buffalo
country: United States
state: New York
city: New York
country: United States
state: New York
city: Cleveland
country: United States
state: Ohio
city: Oklahoma City
country: United States
state: Oklahoma
city: Philadelphia
country: United States
state: Pennsylvania
city: Nashville
country: United States
state: Tennessee
city: Barcelona
country: Spain
city: Valencia
country: Spain
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Monitor
role: STUDY_DIRECTOR
References:
citation: Voss MH, Gordon MS, Mita M, Rini B, Makker V, Macarulla T, Smith DC, Cervantes A, Puzanov I, Pili R, Wang D, Jalal S, Pant S, Patel MR, Neuwirth RL, Enke A, Shou Y, Sedarati F, Faller DV, Burris HA 3rd. Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer. Br J Cancer. 2020 Nov;123(11):1590-1598. doi: 10.1038/s41416-020-01041-x. Epub 2020 Sep 11.