First-in-Human Dose Escalation Trial in Subjects With Advanced Malignancies

Sponsor

EMD Serono (Industry)

Overall Status

Completed

CT.gov ID

NCT01971515

Collaborator

(none)

101

Enrollment

Locations

Arms

55.9

Actual Duration (Months)

6.7

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a Phase 1, first-in-human, open-label, non-randomized, dose escalation, trial to explore the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD) and clinical activity signals of MSC2363318A.

Condition or Disease	Intervention/Treatment	Phase
Solid Tumor	Drug: MSC2363318A Drug: MSC2363318A plus Trastuzumab Drug: MSC2363318A plus Tamoxifen	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

101 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I, First-in-Human, Dose Escalation Trial of MSC2363318A, a Dual p70S6K/Akt Inhibitor, in Subjects With Advanced Malignancies

Actual Study Start Date :

Dec 13, 2013

Actual Primary Completion Date :

Aug 9, 2018

Actual Study Completion Date :

Aug 9, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MSC2363318A	Drug: MSC2363318A Part 1: MSC2363318A will be administered orally once daily for repeated 21-day cycles until intolerable toxicity or disease progression. Additional dose escalations will continue until Maximum Tolerated Dose (MTD) is reached, the food effect will be investigated in a separate group. Part 2 (Cohort 1): MSC2363318A will be administered orally once daily for repeated 21-day cycles until intolerable toxicity or disease progression in subjects with PAM pathway alterations. Dose reductions or treatment interruptions will be made at the discretion of the Investigator. If treatment interruption is required due to an acute or less severe but intolerable MSC2363318A-related event, at least a 1-week break is recommended. If, at retreatment, the dose reduction is not required, then the "continuous daily dosing regimen" may be replaced with an "intermittent dose regimen" of 2 weeks on, 1 week off (i.e. daily dosing from Day 1 to Day 15 followed by no dosing on Day 16 to Day 21 of the cycle). Other Names: M2698
Experimental: MSC2363318A plus Trastuzumab	Drug: MSC2363318A plus Trastuzumab Part 2 Cohort 2: MSC2363318A will be administered orally once daily for repeated 21-day cycles in combination with Trastuzumab. Dose reductions or treatment interruptions will be made at the discretion of the Investigator. If treatment interruption is required due to an acute or less severe but intolerable MSC2363318A-related event, at least a 1-week break is recommended. If, at retreatment, the dose reduction is not required, then the "continuous daily dosing regimen" may be replaced with an "intermittent dose regimen" of 2 weeks on, 1 week off (i.e. daily dosing from Day 1 to Day 15 followed by no dosing on Day 16 to Day 21 of the cycle). Trastuzumab is a recombinant IgGI kappa humanized monoclonal antibody administered weekly by intravenous infusion.
Experimental: MSC2363318A plus Tamoxifen	Drug: MSC2363318A plus Tamoxifen Part 2 Cohort 3: MSC2363318A will be administered orally once daily for repeated 21-day cycles in combination with Tamoxifen. Dose reductions or treatment interruptions will be made at the discretion of the Investigator. If treatment interruption is required due to an acute or less severe but intolerable MSC2363318A-related event, at least a 1-week break is recommended. If, at retreatment, the dose reduction is not required, then the "continuous daily dosing regimen" may be replaced with an "intermittent dose regimen" of 2 weeks on, 1 week off (i.e. daily dosing from Day 1 to Day 15 followed by no dosing on Day 16 to Day 21 of the cycle). Tamoxifen is a nonsteroidal antiestrogen administered daily by oral administration.

Arm

Intervention/Treatment

Experimental: MSC2363318A

Drug: MSC2363318A

Part 1: MSC2363318A will be administered orally once daily for repeated 21-day cycles until intolerable toxicity or disease progression. Additional dose escalations will continue until Maximum Tolerated Dose (MTD) is reached, the food effect will be investigated in a separate group. Part 2 (Cohort 1): MSC2363318A will be administered orally once daily for repeated 21-day cycles until intolerable toxicity or disease progression in subjects with PAM pathway alterations. Dose reductions or treatment interruptions will be made at the discretion of the Investigator. If treatment interruption is required due to an acute or less severe but intolerable MSC2363318A-related event, at least a 1-week break is recommended. If, at retreatment, the dose reduction is not required, then the "continuous daily dosing regimen" may be replaced with an "intermittent dose regimen" of 2 weeks on, 1 week off (i.e. daily dosing from Day 1 to Day 15 followed by no dosing on Day 16 to Day 21 of the cycle).

Other Names:

M2698

Experimental: MSC2363318A plus Trastuzumab

Drug: MSC2363318A plus Trastuzumab

Part 2 Cohort 2: MSC2363318A will be administered orally once daily for repeated 21-day cycles in combination with Trastuzumab. Dose reductions or treatment interruptions will be made at the discretion of the Investigator. If treatment interruption is required due to an acute or less severe but intolerable MSC2363318A-related event, at least a 1-week break is recommended. If, at retreatment, the dose reduction is not required, then the "continuous daily dosing regimen" may be replaced with an "intermittent dose regimen" of 2 weeks on, 1 week off (i.e. daily dosing from Day 1 to Day 15 followed by no dosing on Day 16 to Day 21 of the cycle). Trastuzumab is a recombinant IgGI kappa humanized monoclonal antibody administered weekly by intravenous infusion.

Experimental: MSC2363318A plus Tamoxifen

Drug: MSC2363318A plus Tamoxifen

Part 2 Cohort 3: MSC2363318A will be administered orally once daily for repeated 21-day cycles in combination with Tamoxifen. Dose reductions or treatment interruptions will be made at the discretion of the Investigator. If treatment interruption is required due to an acute or less severe but intolerable MSC2363318A-related event, at least a 1-week break is recommended. If, at retreatment, the dose reduction is not required, then the "continuous daily dosing regimen" may be replaced with an "intermittent dose regimen" of 2 weeks on, 1 week off (i.e. daily dosing from Day 1 to Day 15 followed by no dosing on Day 16 to Day 21 of the cycle). Tamoxifen is a nonsteroidal antiestrogen administered daily by oral administration.

Outcome Measures

Primary Outcome Measures

Number of dose limiting toxicities (DLTs) in Dose Escalation and Trastuzumab or Tamoxifen combination arms [Up to Day 21 of Cycle 1]
Number of subjects with Treatment-emergent adverse events (TEAEs), Serious Adverse Events (SAEs), and deaths in cohort for subjects with PAM pathway alterations [Baseline up to Day 30 after the last dose of study treatment]

Secondary Outcome Measures

Observed Maximum Plasma Concentration (Cmax) [Days 1, 2, 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2, Cycle 3]
Time To Reach Maximum Plasma Concentration (Tmax) [Days 1, 2, 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2, Cycle 3]
Area Under Plasma Concentration Versus Time Curve From Time Zero to Last Sampling Time (AUC0-t) [Days 1, 2, 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2, Cycle 3]
Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) [Days 1, 2, 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2, Cycle 3]
Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) [Days 1, 2, 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2, Cycle 3]
Apparent Terminal Half-life ( t1/2) [Days 1, 2, 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2, Cycle 3]
Apparent Oral Clearance (CL/F) [Days 1, 2, 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2, Cycle 3]
Apparent Oral Clearance Steady State (CLss/F) [Days 1, 2, 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2, Cycle 3]
Apparent Volume of Distribution (Vz/F) [Days 1, 2, 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2, Cycle 3]
Apparent Volume of Distribution at Steady State (Vss/F) [Days 1, 2, 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2, Cycle 3]
Factor to Assess the Increase of Drug Concentration in Plasma Until Steady State is Reached [Racc(AUC)] [Days 1, 2, 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2, Cycle 3]
Factor to Assess the Maximal Increase of Drug Concentration in Plasma [Racc (Cmax)] [Days 1, 2, 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2, Cycle 3]
Number of subjects with best overall response according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v 1.1) or Cheson 2007 [Evaluation were performed on Day 1 of every alternate cycle until tumor progression]
Percentage of subjects with clinical benefit [Week 12]
Percentage of subjects with clinical benefit is defined as subjects with complete response (CR) or partial response (PR) at week 12, based on tumor assessment as determined by RECIST version 1.1 or Cheson 2007.
Disease control rate (DCR) for Cohort 2 only [Week 6]
Progression-free survival (PFS) rate for Cohorts 2 and 3 only [up to 6 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age greater than or equal to (>=)18 years
Confirmed diagnosis of advanced malignancies that may be controlled with p70S6K or Akt inhibition based on already identified molecular alteration known to affect the PAM pathway, such as:: such as: such as: phosphate and tensin homolog (PTEN), phosphoinositide 3-Kinase catalytic subunit alpha isoform (PIK3CA), protein kinase B 1 (Akt 1), Akt 3, mammalian target of rapamycin (mTOR), tumor sclerosis complex 1 (TSC1), tumor sclerosis complex 2 (TSC2), in subjects who have received at least all treatment options considered to be standard therapy, unless some available treatment are not acceptable to the subject. For the dose escalation portion of the trial, subjects must have received the standard therapy unless intolerant or contraindicated.
Part 2, Cohort 1: For subjects with only PAM pathway alterations, subjects must have only PAM alterations, excluding Akt2 activating mutations or amplifications, and no other genomic alterations.
Part 2, Cohort 2: Histologically confirmed local laboratory testing (immunohistochemistry 3+ staining and/or fluorescence in situ hybridization ratio

= 2.0) HER2+ metastatic breast cancer subjects who are resistant to trastuzumab-containing treatment and progressed on trastuzumab, pertuzumab, a taxane, and/or trastuzumab emtansine. There is no limit regarding the number of prior lines of therapy. Subjects may be enrolled regardless of whether or not their tumor harbors a PAM pathway alteration (documentation of PAM pathway alteration for this cohort is not required).

Part 2, Cohort 3: Histologically and/or cytologically confirmed diagnosis of breast cancer with hormone receptor-positive status (ER and/or PgR positive) and HER2-negative status with prior exposure to tamoxifen and/or an aromatase inhibitor and/or an aromatase inhibitor plus palbociclib. Prior treatment with tamoxifen in the neoadjuvant setting is allowed but must have been discontinued for at least 1 year prior to the first dose.
Measurable disease using clinically appropriate criteria for the type of malignancy, RECIST version 1.1 for solid tumors and Cheson 2007 for lymphoma
A tumor accessible for biopsies and consent to undergo tumor biopsies before and during MSC2363318A treatment. Subjects who do not have a tumor suitable for biopsy (such as, but not limited to, high procedural risk, inaccessible site for needle biopsy, etc.) but are otherwise eligible for this study may be considered for enrollment on a case-by-case basis after discussion with the Medical Monitor of the study
Ability to read and understand the informed consent form and willingness and ability to give informed consent and demonstrate comprehension of the trial before undergoing any trial activities
Negative blood pregnancy test at the screening visit for women of childbearing potential
Willingness to avoid pregnancy and breast feeding beginning two weeks before the first MSC2363318A dose and ending three months after the last trial treatment. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must use adequate contraception in the judgment of the Investigator, such as a two barrier method or a one barrier method with spermicide or intrauterine device during trial treatment dosing and for 3 months after the last dose of the study.

Exclusion Criteria:

Eastern Cooperative Oncology Group Performance Status >=2
Previous therapy with:
Chemotherapy, immunotherapy, biologic therapy, or any other anticancer therapy within 2 weeks (or five elimination half lives for noncytotoxics, whichever is shorter) of Day 1 of trial drug treatment (6 weeks for nitrosureas or mitomycin). Subjects on therapy with trastuzumab (trastuzumab cohort) may continue with trastuzumab during the screening phase of the study. Subjects on endocrine therapy may continue with antihormonal therapy until Day 1 of the study.
Any investigational agent within 3 weeks of Day 1 of trial drug treatment
Extensive prior radiotherapy on more than 30 percent of bone marrow reserves, or prior bone marrow/stem cell transplantation within 5 years from enrolment
Palliative radiation therapy within 2 weeks of Day 1 of trial drug treatment
Known tumor EGFR, KRAS, and/or Akt2 mutations or amplification
Ongoing toxicity due to a prior therapy, unless returned to baseline or Grade 1. Grade 2 toxicities (e.g., alopecia or peripheral neuropathy) that are not likely to increase the subject's safety risk while receiving trial treatment may be accepted after Sponsor approval.
Major surgical intervention or participation in a therapeutic clinical trial within 28 days from Day 1 of the first dose of MSC2363318A
Bone marrow impairment, renal impairment, liver function abnormality and impaired cardiac function as defined in the protocol
History of cerebral vascular accident or stroke within the previous 2 years
Uncontrolled hypertension
History of Grade 3 or 4 allergic reactions attributed to compounds of similar chemical or biologic composition as MSC2363318A
Known symptomatic central nervous system (CNS) metastases
History of difficulty swallowing, malabsorption or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the investigational product
Known human immunodeficiency virus, viral hepatitis, or tuberculosis positivity
Legal incapacity or limited legal capacity
Any other condition which, in the opinion of the Investigator, might impair the subject's tolerance of trial treatment, the safety of the individual subject or the outcome of the trial. (including but not limited to: history of major depressive episode, bipolar disorder, obsessive-compulsive disorder, schizophrenia, suicidal attempt or ideation, homicidal ideation, or >= Common Terminology Criteria for Adverse Events [CTCAE] Grade 3 anxiety)
Immediate prior therapy with a PAM pathway inhibitor (i.e., the subject is excluded if the last treatment regimen, prior to MSC2363318A, was a PAM pathway inhibitor, or if the last PAM pathway inhibitor that the subject was treated with occured less than 2 months prior to Day 1 of trial drug treatment).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	Cedars Sinai Medical Center	Los Angeles	California	United States	90048
3	University of California at San Diego, Moores Cancer Center	San Diego	California	United States	92093
4	Sylvester Comprehensive Cancer Center	Miami	Florida	United States	33136
5	Metairie Oncology	Metairie	Louisiana	United States	70006
6	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
7	Karmanos Cancer Institute	Detroit	Michigan	United States	48201
8	Henry Ford Hospital	Detroit	Michigan	United States	48202
9	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
10	Mount Sinai	New York	New York	United States	10029
11	Medical University of South Carolina	Charleston	South Carolina	United States	29425
12	Mary Crowley Cancer Research Center	Dallas	Texas	United States	75251
13	MD Anderson Cancer Center	Houston	Texas	United States	77030
14	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229
15	Fletcher Allen Health Care, Inc.	Burlington	Vermont	United States	05401