A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Hormone Receptor-Positive HER2-Negative Breast Cancer (MORPHEUS-HR+ Breast Cancer)

A Study of Multiple Immunotherapy-Based Treatment Combinations in Hormone Receptor (HR)-Positive Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Breast Cancer



Sponsors

Lead Sponsor



Source

Hoffmann-La Roche

Oversight Info

Is Fda Regulated Drug

Yes

Is Fda Regulated Device

No


Brief Summary

This study is designed to evaluate the efficacy, safety, and pharmacokinetics of several
immunotherapy-based combination treatments in participants with metastatic HR-positive,
HER2-negative breast cancer who have progressed during or following first-line metastatic
treatment with a cyclin-dependent kinase (CDK) 4/6 inhibitor such as palbociclib, ribociclib,
or abemaciclib. The study will be performed in two stages. During Stage 1, participants will
be randomized to fulvestrant (control) or an atezolizumab-containing doublet or triplet
combination. Those who experience disease progression, loss of clinical benefit, or
unacceptable toxicity may be eligible to receive a new triplet combination treatment in Stage
2 until loss of clinical benefit or unacceptable toxicity. New treatment arms may be added
and/or existing treatment arms may be closed during the course of the study on the basis of
ongoing clinical efficacy and safety as well as the current treatments available.

Overall Status

Not yet recruiting

Start Date

2017-09-30

Completion Date

2022-10-07

Primary Completion Date

2021-04-30

Phase

Phase 1/Phase 2

Study Type

Interventional

Primary Outcome

Measure

Time Frame

Percentage of Participants with Objective Response during Stage 1 According to Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1
From baseline until disease progression or loss of clinical benefit (up to 6 years overall)

Secondary Outcome

Measure

Time Frame

Progression-Free Survival during Stage 1 According to RECIST v1.1
From randomization until disease progression or death from any cause (up to 6 years overall)
Percentage of Participants with Clinical Benefit during Stage 1 According to RECIST v1.1
From baseline until disease progression or loss of clinical benefit (up to 6 years overall)
Overall Survival during Stage 1
From randomization until death from any cause (up to 6 years overall)
Percentage of Participants Alive at 18 Months during Stage 1
18 months
Duration of Response during Stage 1 According to RECIST v1.1
From first objective response until disease progression or death from any cause (up to 6 years overall)
Percentage of Participants with Adverse Events (AEs) during Stage 1
From baseline until 30 days after last dose or initiation of new systemic anti-cancer therapy (up to 6 years overall)
Percentage of Participants with AEs during Stage 2
From baseline until 30 days after last dose or initiation of new systemic anti-cancer therapy (up to 6 years overall)
Atezolizumab Serum Concentration during Stage 1
Predose (0 hours [h]) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (cycle = 28 days); postdose (30 minutes [min]) (infusion = 30-60 min) on Day 1 of Cycle 1; at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)
Cobimetinib Plasma Concentration during Stage 1
Predose (0 h) and postdose (2-4 h) on Day 15 of Cycle 1 (cycle = 28 days)
Fulvestrant Plasma Concentration during Stage 1
Predose (0 h) on Day 1 of Cycles 2-3 (cycle = 28 days)
Ipatasertib Plasma Concentration during Stage 1
Predose (0 h) on Day 1 of Cycle 1 (cycle = 28 days); predose (0 h) and postdose (1-3, 4, 6 h) on Day 15 of Cycle 1; postdose (1-3 h) on Day 15 of Cycle 3
Atezolizumab Serum Concentration during Stage 2
Predose (0 h) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (cycle = 21-28 days); postdose (30 min) (infusion = 30-60 min) on Day 1 of Cycle 1; at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)
Bevacizumab Serum Concentration during Stage 2
Predose (0 h) and postdose (30 min) (infusion = 30-90 min) on Day 1 of Cycles 1, 3 (cycle = 21-28 days); at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)
Exemestane Plasma Concentration during Stage 2
Predose (0 h) on Day 15 of Cycle 1 and Day 1 of Cycle 2 (cycle = 21 days)
Fulvestrant Plasma Concentration during Stage 2
Predose (0 h) on Day 1 of Cycles 2-3 (cycle = 28 days)
Tamoxifen Plasma Concentration during Stage 2
Predose (0 h) on Day 15 of Cycle 1 and Day 1 of Cycle 2 (cycle = 21 days)
Percentage of Participants with Anti-Drug Antibodies (ADAs) to Atezolizumab during Stage 1
Predose (0 h) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (cycle = 28 days); at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)
Percentage of Participants with ADAs to Atezolizumab during Stage 2
Predose (0 h) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (cycle = 21-28 days); at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)
Percentage of Participants with ADAs to Bevacizumab during Stage 2
Predose (0 h) on Day 1 of Cycles 1, 3 (cycle = 21-28 days); at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)

Enrollment

111

Condition


Intervention

Intervention Type

Drug

Intervention Name


Description

Atezolizumab will be given as 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. This regimen will apply to all arms except when given with exemestane or tamoxifen in Stage 2, in which atezolizumab will be given as 1200 mg via IV infusion on Day 1 of each 21-day cycle.

Arm Group Label

Stage 1: Atezolizumab + Cobimetinib

Stage 1: Atezolizumab + Fulvestrant

Stage 1: Atezolizumab + Ipatasertib

Stage 1: Atezolizumab + Ipatasertib + Fulvestrant

Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy

Stage 1: Mandatory On-Treatment Biopsy


Other Name

Tecentriq


Intervention Type

Drug

Intervention Name


Description

Bevacizumab will be given as 10 milligrams per kilogram (mg/kg) via IV infusion on Days 1 and 15 of each 28-day cycle in the regimen containing fulvestrant. When given with exemestane or tamoxifen, bevacizumab will be given as 15 mg/kg via IV infusion on Day 1 of each 21-day cycle.

Arm Group Label

Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy

Other Name

Avastin


Intervention Type

Drug

Intervention Name


Description

Cobimetinib will be given as 60 mg orally once a day (QD) on Days 1-21 of each 28-day cycle.

Arm Group Label

Stage 1: Atezolizumab + Cobimetinib

Stage 1: Mandatory On-Treatment Biopsy


Other Name

Cotellic


Intervention Type

Drug

Intervention Name


Description

Exemestane will be given as 25 mg orally QD in each 21-day cycle.

Arm Group Label

Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy


Intervention Type

Drug

Intervention Name


Description

Fulvestrant will be given as 500 mg intramuscularly on Days 1 and 15 of Cycle 1 and thereafter on Day 1 of each 28-day cycle.

Arm Group Label

Stage 1: Fulvestrant

Stage 1: Atezolizumab + Fulvestrant

Stage 1: Atezolizumab + Ipatasertib + Fulvestrant

Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy

Stage 1: Mandatory On-Treatment Biopsy



Intervention Type

Drug

Intervention Name


Description

Ipatasertib will be given as 400 mg orally QD on Days 1-21 of each 28-day cycle.

Arm Group Label

Stage 1: Atezolizumab + Ipatasertib

Stage 1: Atezolizumab + Ipatasertib + Fulvestrant

Stage 1: Mandatory On-Treatment Biopsy



Intervention Type

Drug

Intervention Name


Description

Tamoxifen will be given as 20 mg orally QD in each 21-day cycle.

Arm Group Label

Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy



Eligibility

Criteria

Inclusion Criteria for Both Stages:

- Measureable disease per RECIST v1.1 with tumor accessible for biopsy

- Adequate hematologic and end organ function

Inclusion Criteria for Stage 1:

- Eastern Cooperative Oncology Group (ECOG) performance status 0-1

- Metastatic or inoperable, locally advanced, histologically or cytologically confirmed
invasive HR-positive HER2-negative breast cancer

- Recommended for endocrine therapy, and cytotoxic chemotherapy not indicated at study
entry

- Recurrence or progression following most recent systemic breast cancer therapy

- Disease progression during or after CDK4/6 inhibitor treatment for metastatic disease

- Postmenopausal according to protocol-defined criteria

- Life expectancy >3 years

- Available tumor specimen for determination of PD-L1 status

Inclusion Criteria for Stage 2:

- ECOG performance status of 0-2

- Ability to initiate treatment within 3 months after disease progression or
unacceptable toxicity on a Stage 1 regimen

Exclusion Criteria for Both Stages:

- Significant or uncontrolled comorbid disease as specified in the protocol

- Uncontrolled tumor-related pain

- Autoimmune disease except for stable/controlled hypothyroidism, Type 1 diabetes
mellitus, or certain dermatologic conditions

- Positive human immunodeficiency virus or hepatitis B or C

- Severe infection within 4 weeks and/or antibiotics within 2 weeks prior to study
treatment

- Prior allogeneic stem cell or solid organ transplantation

- History of malignancy other than breast cancer within 2 years prior to screening
except those with negligible risk of metastasis/death

- History of or known hypersensitivity to study drug or excipients

Exclusion Criteria for Stage 1:

- HER2-positive breast cancer

- Prior fulvestrant or cytotoxic chemotherapy for metastatic breast cancer, or certain
other agents as specified in the protocol

- Unresolved AEs from prior anti-cancer therapy

Exclusion Criteria for Stage 2:

- Unacceptable toxicity with atezolizumab during Stage 1

- Uncontrolled cardiovascular disease or coagulation disorder, including use of
anticoagulants as specified in the protocol

- Significant abdominal or intestinal manifestations within 6 months prior to treatment

- Proteinuria

Gender

Female

Minimum Age

18 Years

Maximum Age

N/A

Healthy Volunteers

No


Overall Official

Last Name

Role

Affiliation

Clinical Trials
Study Director
Hoffmann-La Roche

Overall Contact

Last Name

Reference Study ID Number: CO39611 www.roche.com/about_roche/roche_worldwide.htm

Phone

888-662-6728 (U.S. and Canada)

Email



Location

Facility

Status

University of Alabama at Birmingham
Birmingham Alabama 35249 United States
Not yet recruiting
UCSF Helen Diller Family CCC
San Francisco California 94115 United States
Not yet recruiting
Yale University School Of Medicine; Yale Cancer Center
Trumbull Connecticut 06611 United States
Not yet recruiting
Northwest Georgia Oncology Centers PC - Marietta
Marietta Georgia 30060 United States
Not yet recruiting
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
Baltimore Maryland 21231 United States
Not yet recruiting
University of Michigan
Ann Arbor Michigan 48109-0934 United States
Not yet recruiting
Memorial Sloan Kettering Cancer Center
New York New York 10065 United States
Not yet recruiting
Levine Cancer Institute
Charlotte North Carolina 28204 United States
Not yet recruiting
Providence Cancer Center
Portland Oregon 97231 United States
Not yet recruiting
University of Pittsburgh Medical Center Health System; Dept. of Newborn Medicine
Pittsburgh Pennsylvania 15213 United States
Not yet recruiting
Tennessee Oncology; Sarah Cannon Cancer Center
Nashville Tennessee 37203 United States
Not yet recruiting
Northwest Medical Specialties, PLLC; Research Department
Tacoma Washington 98405 United States
Not yet recruiting

Location Countries

Country

United States


Verification Date

2017-09-01

Lastchanged Date

2017-09-11

Firstreceived Date

2017-09-11

Responsible Party

Responsible Party Type

Sponsor


Has Expanded Access

No

Condition Browse


Secondary Id

2017-000335-14

Number Of Arms

7

Intervention Browse

Mesh Term

Bevacizumab

Fulvestrant

Exemestane

Tamoxifen

Antibodies

Antibodies, Monoclonal

Hormones

Estradiol



Arm Group

Arm Group Label

Stage 1: Fulvestrant

Arm Group Type

Active Comparator

Description

Participants will receive fulvestrant until unacceptable toxicity or disease progression according to RECIST v1.1.


Arm Group Label

Stage 1: Atezolizumab + Cobimetinib

Arm Group Type

Experimental

Description

Participants will receive doublet combination treatment with atezolizumab plus cobimetinib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.


Arm Group Label

Stage 1: Atezolizumab + Fulvestrant

Arm Group Type

Experimental

Description

Participants will receive doublet combination treatment with atezolizumab plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator.


Arm Group Label

Stage 1: Atezolizumab + Ipatasertib

Arm Group Type

Experimental

Description

Participants will receive doublet combination treatment with atezolizumab plus ipatasertib until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Prior to enrollment into this arm, the first 6 participants in the study will complete a safety run-in with atezolizumab plus ipatasertib.


Arm Group Label

Stage 1: Atezolizumab + Ipatasertib + Fulvestrant

Arm Group Type

Experimental

Description

Participants will receive triplet combination treatment with atezolizumab plus ipatasertib plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Prior to enrollment into this arm, the first 6 participants in the study will complete a safety run-in with atezolizumab plus ipatasertib.


Arm Group Label

Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy

Arm Group Type

Experimental

Description

Those who progress or experience unacceptable toxicity during treatment in Stage 1 may be eligible to enter Stage 2. Participants will receive triplet combination therapy with atezolizumab plus bevacizumab plus one of three endocrine therapies (fulvestrant, exemestane, or tamoxifen) selected by the physician. Treatment in Stage 2 will continue until unacceptable toxicity or loss of clinical benefit as determined by the investigator.


Arm Group Label

Stage 1: Mandatory On-Treatment Biopsy

Arm Group Type

Experimental

Description

For experimental combination arms that demonstrate clinical activity during the preliminary phase, the Sponsor may open enrollment into a separate mandatory on-treatment biopsy cohort for that combination.



Firstreceived Results Date

N/A

Acronym

MORPHEUS

Firstreceived Results Disposition Date

N/A

Study Design Info

Allocation

Randomized

Intervention Model

Sequential Assignment

Primary Purpose

Treatment

Masking

None (Open Label)



ClinicalTrials.gov processed this data on September 13, 2017

Conditions

Conditions usually refer to a disease, disorder, syndrome, illness, or injury. In ClinicalTrials.gov, conditions include any health issue worth studying, such as lifespan, quality of life, health risks, etc.
Interventions

Interventions refer to the drug, vaccine, procedure, device, or other potential treatment being studied. Interventions can also include less intrusive possibilities such as surveys, education, and interviews.
Study Phase

Most clinical trials are designated as phase 1, 2, 3, or 4, based on the type of questions that study is seeking to answer:

In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.

In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.

In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.

These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.



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