Trial of Exemestane +/- MM-121 in Postmenopausal Women With Locally Advanced or Metastatic Estrogen Receptor Positive and/or Progesterone Receptor Positive Her2 Negative Breast Cancer

• Sponsor: Merrimack Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01151046
• Collaborator: (none)
• Enrollment: 118
• Locations: 33
• Arms: 2
• Duration (Months): 51
• Patients Per Site: 3.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

To determine whether the combination MM-121 + Exemestane in ER+ and/or PR+ breast cancer patients is more effective than Exemestane alone

Condition or Disease	Intervention/Treatment	Phase
Her2 Negative Breast Cancer Patients	Drug: MM-121; Drug: Placebo; Drug: Exemestane	Phase 2

Detailed Description

The study is a double-blind, randomized Phase 2 trial of Exemestane +/- MM-121. The trial is designed to demonstrate whether MM-121 + Exemestane is more effective than Exemestane alone in ER+ and/or PR+ and Her2 negative breast cancer patients that have failed first-line anti-estrogen therapy in the locally advanced or metastatic setting and patients that have progressed during (or within 6 months of completing) adjuvant treatment with a non-steroidal aromatase inhibitor (AI)and/or tamoxifen. Patients will be treated until radiologic or clinical progression of their disease is documented. Local radiologist and/or PI assessment is accepted.

Study Design

• Study Type: Interventional
• Actual Enrollment: 118 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized Double-Blind Phase 2 Trial of Exemestane +/- MM-121 in Postmenopausal Women With Locally Advanced or Metastatic Estrogen Receptor Positive (ER+) and/or Progesterone Receptor Positive (PR+) Her2 Negative Breast Cancer
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: Jun 1, 2014
• Actual Study Completion Date: Sep 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MM-121 (SAR256212) + exemestane	Drug: MM-121; MM-121 (40mg/kg loading dose week 1, then 20 mg/kg weekly) administered over 60 minutes as an intravenous infusion once per week; Other Names: SAR256212 ; Drug: Exemestane; Exemestane (25 mg) administered orally once per day; Other Names: Aromasin
Placebo Comparator: Placebo + exemestane	Drug: Placebo; Placebo (histidine solution) administered over 60 minutes as an intravenous infusion once per week and exemestane (25 mg) administered orally once per day; Drug: Exemestane; Exemestane (25 mg) administered orally once per day; Other Names: Aromasin

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) [Time from first dose to date of progression, the longest time frame of 79.1 weeks]

   To determine whether MM-121 + exemestane was more effective than placebo + exemestane in prolonging progression-free survival. PFS was a time to event measure, and progression of disease is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), "as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions". Progression free survival was defined as the number of months from the date of randomization to the date of death or progression. If neither death nor progression was observed during the study, PFS data was censored at the last non-progressive disease valid tumor assessment unless the patient was discontinued due to symptomatic deterioration. If this occurred, the patient was counted as having progressive disease (PD).

Secondary Outcome Measures

1. Overall Survival [Time from first dose to date of death, over approximately 2 years]

   To determine whether MM-121 + exemestane is more effective than placebo + exemestane in prolonging overall survival. This was a time-to-event analysis of time from first dose to date of death.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Locally advanced or metastatic breast cancer

• Histologically or cytologically confirmed ER+ and/or PgR+ and Her2 negative breast cancer

• ≥ 18 years of age

Exclusion Criteria:

• Received prior treatment with exemestane

• Extensive visceral disease (rapidly progressive, life-threatening metastases, including symptomatic lymphangitic metastases)

• Symptomatic CNS disease

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Achieve Clinical Research	Birmingham	Alabama	United States	35209
2	Achieve Clinical Research	Birmingham	Alabama	United States	35216
3	Arizona Center for Cancer Care	Glendale	Arizona	United States	85306
4	Pacific Cancer Medical Center	Anaheim	California	United States	92801
5	Beverly Hills Cancer Center	Beverly Hills	California	United States	90211
6	Wilshire Oncology Medical Group, Inc.	Corona	California	United States	92879
7	Southwest Cancer Center	Escondido	California	United States	92025
8	Hematology Oncology Associates, INC.	Oakland	California	United States	94609
9	San Jose Medical Center	San Jose	California	United States	95124
10	Central Coast Medical Oncology Corporation	Santa Maria	California	United States	93454
11	Pasco-Pinellas Oncology	New Port Richey	Florida	United States	34652
12	Hematology Oncology Associates of the Treasure Coast	Port St. Lucie	Florida	United States	34952
13	Rush University Medical Center	Chicago	Illinois	United States	60612
14	Indiana University Simon Cancer Center	Indianapolis	Indiana	United States	46202
15	Horizon Oncology Center	Lafayette	Indiana	United States	47905
16	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
17	Tennessee Cancer Specialists Oncology Clinical Trials Center for Biomedical Research	Knoxville	Tennessee	United States	37909
18	Tennessee Cancer Specialists, Oncology Clincial Trials Center for Biomedical Research	Knoxville	Tennessee	United States	37909
19	Hopital Maissoneuve-Rosemont	Montreal	Quebec	Canada	H1T2M4
20	McGill University Jewish General Hospital	Montreal	Quebec	Canada	H3T 1E2
21	Hopital du Sacre-Coeur de Montreal	Montreal		Canada	H4J 1C5
22	CHA St. Sacrement	Quebec		Canada	G1S 4L8
23	Onkogologisches zentrum Munich	Munich		Germany	80836
24	Brustzentrum HS Kliniken Wiesbaden	Wiesbaden		Germany	65189
25	Medico-Diagnostically Center of International Institution of biological systems n.a.S.M.	Berezina		Russian Federation
26	Railway Clinical Hospital	St. Petersburg		Russian Federation	125271
27	Leningrad Regional Oncology Center	St. Petersburg		Russian Federation	188663
28	City Clinical Oncology Center	St. Petersburg		Russian Federation	197022
29	Vall d'Hebrón University Hospital	Barcelona		Spain	8035
30	Hospital Clinic (Barcelona)	Barcelona		Spain	8036
31	Hospital Parc Tauli - Barcelona	Barcelona		Spain	8208
32	Servicio de Oncología Médica / Hospital Universitario Gregorio Marañón	Madrid		Spain	28007
33	Puerta de Hierro	Madrid		Spain	28220

Sponsors and Collaborators

• Merrimack Pharmaceuticals

Investigators

• Study Director: Victor Moyo, MD, Merrimack Pharmaceuticals, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merrimack Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01151046
• Other Study ID Numbers: MM-121-02-02-03 (ARD11588)
• First Posted: Jun 25, 2010
• Last Update Posted: May 12, 2016
• Last Verified: Apr 1, 2016

• Keywords provided by Merrimack Pharmaceuticals: Breast Cancer; Her2 negative; Estrogen Receptor Positive; Progesterone Receptor Positive; MM-121; Exemestane; Postmenopausal Women
• Additional relevant MeSH terms: Breast Neoplasms; Exemestane

Study Results

Participant Flow

Arm/Group Title	MM-121 + Exemestane	Placebo + Exemestane
Arm/Group Description	MM-121 (40mg/kg loading dose week 1, then 20 mg/kg weekly) administered over 60 minutes as an intravenous infusion once per week, plus exemestane (25 mg) administered orally once per day	Placebo and Exemestane: Placebo (histidine solution) administered over 60 minutes as an intravenous infusion once per week plus exemestane (25 mg) administered orally once per day
Period Title: Overall Study
STARTED	59	59
COMPLETED	56	59
NOT COMPLETED	3	0

Baseline Characteristics

Arm/Group Title	MM-121 + Exemestane	Placebo + Exemestane	Total
Arm/Group Description	MM-121 and Exemestane: MM-121 (40mg/kg loading dose week 1, then 20 mg/kg weekly) administered over 60 minutes as an intravenous infusion once per week plus exemestane (25 mg) administered orally once per day	Placebo and Exemestane: Placebo (histidine solution) administered over 60 minutes as an intravenous infusion once per week plus exemestane (25 mg) administered orally once per day	Total of all reporting groups
Overall Participants	56	59	115
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	33 58.9%	41 69.5%	74 64.3%
>=65 years	23 41.1%	18 30.5%	41 35.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.8 (10.43)	60.5 (9.13)	61.6 (9.81)
Sex: Female, Male (Count of Participants)
Female	56 100%	59 100%	115 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 1.8%	3 5.1%	4 3.5%
Not Hispanic or Latino	55 98.2%	56 94.9%	111 96.5%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	2 3.4%	2 1.7%
Black or African American	2 3.6%	0 0%	2 1.7%
White	54 96.4%	57 96.6%	111 96.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Bone-Only Disease (Y/N) (participants) [Number]
Bone-Only (Yes)	12 21.4%	17 28.8%	29 25.2%
Bone-Only (No)	44 78.6%	42 71.2%	86 74.8%
Progression Setting (Adjuvant, Metastatic) (participants) [Number]
Adjuvant	22 39.3%	22 37.3%	44 38.3%
Metastatic	34 60.7%	37 62.7%	71 61.7%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS)
Description	To determine whether MM-121 + exemestane was more effective than placebo + exemestane in prolonging progression-free survival. PFS was a time to event measure, and progression of disease is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), "as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions". Progression free survival was defined as the number of months from the date of randomization to the date of death or progression. If neither death nor progression was observed during the study, PFS data was censored at the last non-progressive disease valid tumor assessment unless the patient was discontinued due to symptomatic deterioration. If this occurred, the patient was counted as having progressive disease (PD).
Time Frame	Time from first dose to date of progression, the longest time frame of 79.1 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MM-121 + Exemestane	Placebo + Exemestane
Arm/Group Description	MM-121 (40mg/kg loading dose week 1, then 20 mg/kg weekly) administered over 60 minutes as an intravenous infusion once per week, plus exemestane (25 mg) administered orally once per day	Placebo and Exemestane: Placebo (histidine solution) administered over 60 minutes as an intravenous infusion once per week plus exemestane (25 mg) administered orally once per day
Measure Participants	56	59
Median (95% Confidence Interval) [weeks]	15.9	10.7

2. Post-Hoc Outcome

Title	To Explore the Utility of an EGFR Family Receptor-ligand (Heregulin, HRG) as a Predictor of Response to MM-121 and /or Exemestane in Formalin Fixed (FFPE) Tumor Samples
Description	Fresh tumor samples were obtained from patients prior to enrollment and formalin-fixed for analysis. Samples were analyzed using RT-PCR for the expression of the biomarker, heregulin. Progression-free survival was assessed using RECIST v 1.1 to determine whether patients whose tumors express HRG have a lower PFS than those whose tumors do not express HRG, and to assess whether the addition of MM-121 to exemestane can increase PFS in HRG-high patients.
Time Frame	Time from first dose to date of progression, the longest time frame of 79.1 weeks

Outcome Measure Data

Analysis Population Description

Patients with available tissue for RT-PCR analysis

Arm/Group Title	HRG High: MM-121 + Exemestane	HRG High: Placebo + Exemestane	HRG Low: Placebo + Exemestane	HRG Low: MM-121 + Exemestane
Arm/Group Description	MM-121 (40mg/kg loading dose week 1, then 20 mg/kg weekly) administered over 60 minutes as an intravenous infusion once per week, plus exemestane (25 mg) administered orally once per day	Placebo and Exemestane: Placebo (histidine solution) administered over 60 minutes as an intravenous infusion once per week plus exemestane (25 mg) administered orally once per day	Placebo and Exemestane: Placebo (histidine solution) administered over 60 minutes as an intravenous infusion once per week plus exemestane (25 mg) administered orally once per day	MM-121 (40mg/kg loading dose week 1, then 20 mg/kg weekly) administered over 60 minutes as an intravenous infusion once per week, plus exemestane (25 mg) administered orally once per day
Measure Participants	16	18	19	23
Median (95% Confidence Interval) [months PFS]	3.8	1.9	5.4	3.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MM-121 + Exemestane, Placebo + Exemestane
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.26
	Confidence Interval	(2-Sided) 95%; 0.11 to 0.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	HRG Low: Placebo + Exemestane, HRG Low: MM-121 + Exemestane
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.349
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.41
	Confidence Interval	(2-Sided) 95%; 0.69 to 2.88
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Overall Survival
Description	To determine whether MM-121 + exemestane is more effective than placebo + exemestane in prolonging overall survival. This was a time-to-event analysis of time from first dose to date of death.
Time Frame	Time from first dose to date of death, over approximately 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MM-121 + Exemestane	Placebo + Exemestane
Arm/Group Description	MM-121 (40mg/kg loading dose week 1, then 20 mg/kg weekly) administered over 60 minutes as an intravenous infusion once per week, plus exemestane (25 mg) administered orally once per day	Placebo and Exemestane: Placebo (histidine solution) administered over 60 minutes as an intravenous infusion once per week plus exemestane (25 mg) administered orally once per day
Measure Participants	56	59
Median (95% Confidence Interval) [weeks]	NA	96.3

Adverse Events

Time Frame	AEs were collected from a patient's first dose until 30 days after treatment termination. SAEs were collected from time of informed consent until 30 days after termination. If related, events could be reported at any time after termination.
Adverse Event Reporting Description	All related AEs ongoing at treatment discontinuation were followed until resolution. Investigators were to report any AEs/SAEs assumed to be related any time, even if occurring more than 30 days after last dose. Though different for each patient, on average, patients could be followed for related AEs/SAEs for up to 2 years after termination.
Arm/Group Title	MM-121 + Exemestane		Placebo + Exemestane
Arm/Group Description	MM-121 (40mg/kg loading dose week 1, then 20 mg/kg weekly) administered over 60 minutes as an intravenous infusion once per week, plus exemestane (25 mg) administered orally once per day		Placebo and Exemestane: Placebo (histidine solution) administered over 60 minutes as an intravenous infusion once per week plus exemestane (25 mg) administered orally once per day
All Cause Mortality
	MM-121 + Exemestane		Placebo + Exemestane
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	MM-121 + Exemestane		Placebo + Exemestane
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/56 (12.5%)		11/59 (18.6%)
Blood and lymphatic system disorders
Febrile Neutropenia	1/56 (1.8%)	1	0/59 (0%)	0
Cardiac disorders
Cardiovascular insufficiency	1/56 (1.8%)	1	0/59 (0%)	0
Tacchycardia	0/56 (0%)	0	1/59 (1.7%)	1
Gastrointestinal disorders
Abdominal Pain (Upper)	0/56 (0%)	0	1/59 (1.7%)	2
Gastritis	0/56 (0%)	0	1/59 (1.7%)	1
Nausea	2/56 (3.6%)	2	0/59 (0%)	0
Vomiting	1/56 (1.8%)	1	0/59 (0%)	0
General disorders
Chest Pain	1/56 (1.8%)	1	0/59 (0%)	0
Disease Progression	1/56 (1.8%)	1	1/59 (1.7%)	1
Pneumonia	0/56 (0%)	0	1/59 (1.7%)	1
Hepatobiliary disorders
Hepatic Failure	2/56 (3.6%)	2	0/59 (0%)	0
Infections and infestations
Cellulitis	1/56 (1.8%)	1	0/59 (0%)	0
Gastroenteritis Viral	0/56 (0%)	0	1/59 (1.7%)	1
Injury, poisoning and procedural complications
Hip Fracture	0/56 (0%)	0	1/59 (1.7%)	1
Overdose	0/56 (0%)	0	1/59 (1.7%)	1
Metabolism and nutrition disorders
Hyponatremia	1/56 (1.8%)	1	1/59 (1.7%)	1
Musculoskeletal and connective tissue disorders
Back Pain	1/56 (1.8%)	1	0/59 (0%)	0
Pathological Fracture	0/56 (0%)	0	1/59 (1.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to Central Nervous System	0/56 (0%)	0	2/59 (3.4%)	2
Nervous system disorders
Dizziness	1/56 (1.8%)	1	0/59 (0%)	0
Epilepsy	0/56 (0%)	0	1/59 (1.7%)	1
Intracranial hemorrhage	0/56 (0%)	0	1/59 (1.7%)	1
Horner's Syndrome	0/56 (0%)	0	1/59 (1.7%)	1
Respiratory, thoracic and mediastinal disorders
Chronic Obstructive Pulmonary Disease	1/56 (1.8%)	1	0/59 (0%)	0
Pleuritic Pain	1/56 (1.8%)	1	0/59 (0%)	0
Skin and subcutaneous tissue disorders
Skin ulcer	1/56 (1.8%)	1	0/59 (0%)	0
Other (Not Including Serious) Adverse Events
	MM-121 + Exemestane		Placebo + Exemestane
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	48/56 (85.7%)		50/59 (84.7%)
Blood and lymphatic system disorders
Anemia	4/56 (7.1%)		7/59 (11.9%)
Eye disorders
Dry Eye	3/56 (5.4%)		0/59 (0%)
Gastrointestinal disorders
Diarrhea	28/56 (50%)		14/59 (23.7%)
Nausea	16/56 (28.6%)		14/59 (23.7%)
Constipation	6/56 (10.7%)		5/59 (8.5%)
Stomatatitis	6/56 (10.7%)		1/59 (1.7%)
Vomiting	5/56 (8.9%)		9/59 (15.3%)
Abdominal Pain	4/56 (7.1%)		4/59 (6.8%)
Abdominal Pain Upper	3/56 (5.4%)		2/59 (3.4%)
Dyspepsia	3/56 (5.4%)		7/59 (11.9%)
General disorders
Fatigue	13/56 (23.2%)		14/59 (23.7%)
Asthenia	7/56 (12.5%)		6/59 (10.2%)
Influenza-like illness	4/56 (7.1%)		3/59 (5.1%)
Peripheral edema	4/56 (7.1%)		5/59 (8.5%)
Pyrexia	4/56 (7.1%)		4/59 (6.8%)
Chest Pain	3/56 (5.4%)		0/59 (0%)
Hot Flush	3/56 (5.4%)		7/59 (11.9%)
Infections and infestations
Upper Respiratory Tract Infection	4/56 (7.1%)		3/59 (5.1%)
Urinary Tract Infection	4/56 (7.1%)		0/59 (0%)
Cellulitis	3/56 (5.4%)		1/59 (1.7%)
Influenza	3/56 (5.4%)		1/59 (1.7%)
Nasopharyngitis	3/56 (5.4%)		3/59 (5.1%)
Investigations
Aspartate Aminotransferase Increased	7/56 (12.5%)		3/59 (5.1%)
Alanine Aminotransferase Increased	5/56 (8.9%)		2/59 (3.4%)
Weight Decreased	3/56 (5.4%)		3/59 (5.1%)
Metabolism and nutrition disorders
Decreased Appetite	9/56 (16.1%)		5/59 (8.5%)
Hypokalemia	5/56 (8.9%)		2/59 (3.4%)
Hypomagnesemia	5/56 (8.9%)		1/59 (1.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	10/56 (17.9%)		12/59 (20.3%)
Muscle Spasms	8/56 (14.3%)		3/59 (5.1%)
Myalgia	8/56 (14.3%)		6/59 (10.2%)
Pain in Extremity	7/56 (12.5%)		5/59 (8.5%)
Back Pain	6/56 (10.7%)		9/59 (15.3%)
Bone Pain	3/56 (5.4%)		5/59 (8.5%)
Nervous system disorders
Dysgeusia	8/56 (14.3%)		3/59 (5.1%)
Headache	7/56 (12.5%)		12/59 (20.3%)
Dizziness	6/56 (10.7%)		6/59 (10.2%)
Parasthesia	3/56 (5.4%)		3/59 (5.1%)
Psychiatric disorders
Insomnia	7/56 (12.5%)		6/59 (10.2%)
Anxiety	3/56 (5.4%)		0/59 (0%)
Renal and urinary disorders
Pollakuria	3/56 (5.4%)		2/59 (3.4%)
Respiratory, thoracic and mediastinal disorders
Cough	9/56 (16.1%)		10/59 (16.9%)
Dyspnea	8/56 (14.3%)		7/59 (11.9%)
Oropharyngeal Pain	5/56 (8.9%)		2/59 (3.4%)
Sinusitis	4/56 (7.1%)		3/59 (5.1%)
Dyspnea Exertional	3/56 (5.4%)		0/59 (0%)
Skin and subcutaneous tissue disorders
Dry Skin	7/56 (12.5%)		0/59 (0%)
Rash	6/56 (10.7%)		1/59 (1.7%)
Alopecia	6/56 (10.7%)		1/59 (1.7%)
Pruritis	4/56 (7.1%)		6/59 (10.2%)
Rash Maculopapular	3/56 (5.4%)		0/59 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

If no overall study publication has occurred by the Sponsor within 12 months of the completion of this Study, the Investigator shall have the right to publish or present independently the results of this Study subject to the review procedure set forth herein. The Investigator will provide the Sponsor with a copy of any such presentation or publication derived from the Study for review, and the Sponsor may delay publication for up to 90 days to preserve patent activities and proprietary rights.