Trial Outcomes & Findings for Medroxyprogesterone +/- Cyclophosphamide & Methotrexate in Hormone Receptor-Negative Recurrent/Metastatic Breast Cancer (NCT NCT00577122)

Last Updated: 2023-10-16

Results Overview

To determine the clinical benefit rate (Complete Response + Partial Response + Stable Disease \> 6 months) per Response Evaluation Criteria in Solid tumors (RECIST version 1.0). of MPA monotherapy and MPA + low dose oral cyclophosphamide and methotrexate (ldoCM) in patients with refractory hormone receptor negative metastatic breast cancer. This will show the percent of patients who had Clinical Benefit and the Exact 95% Confidence Interval.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

30 participants

Primary outcome timeframe

baseline through end of study, up to 3 years

Results posted on

2023-10-16

Participant Flow

Since there was not enough evidence of clinical benefit, this study did not go beyond the first stage in the two stage design. A total of 30 patients (14 in the MPA alone cohort and 16 in the MPA+ ldoCM cohort) were in the study before the study ended.

Participant milestones

Participant milestones
Measure	Cohort 1: MPA-Alone Medroxyprogesterone progesterone acetate (MPA) will be administered orally as a single daily dose.	Cohort 2: MPA+IdoCM Medroxyprogesterone progesterone acetate (MPA) will be administered orally as a single daily dose. Cyclophosphamide will be administered orally as a single daily dose. Methotrexate will be administered twice daily on days 1 and 2 of each week.
Overall Study STARTED	14	16
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	14	16

Reasons for withdrawal

Reasons for withdrawal
Measure	Cohort 1: MPA-Alone Medroxyprogesterone progesterone acetate (MPA) will be administered orally as a single daily dose.	Cohort 2: MPA+IdoCM Medroxyprogesterone progesterone acetate (MPA) will be administered orally as a single daily dose. Cyclophosphamide will be administered orally as a single daily dose. Methotrexate will be administered twice daily on days 1 and 2 of each week.
Overall Study Adverse Event	0	2
Overall Study Progression, relapse during active trt	6	8
Overall Study Prog, refract disease during active trt	8	5
Overall Study Alternative Therapy	0	1

Baseline Characteristics

Medroxyprogesterone +/- Cyclophosphamide & Methotrexate in Hormone Receptor-Negative Recurrent/Metastatic Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1: MPA-Alone n=14 Participants Medroxyprogesterone progesterone acetate (MPA) will be administered orally as a single daily dose.	Cohort 2: MPA+IdoCM n=16 Participants Medroxyprogesterone progesterone acetate (MPA) will be administered orally as a single daily dose. Cyclophosphamide will be administered orally as a single daily dose. Methotrexate will be administered twice daily on days 1 and 2 of each week.	Total n=30 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	9 Participants n=5 Participants	12 Participants n=7 Participants	21 Participants n=5 Participants
Age, Categorical >=65 years	5 Participants n=5 Participants	4 Participants n=7 Participants	9 Participants n=5 Participants
Age, Continuous	59.0 Years STANDARD_DEVIATION 12.78 • n=5 Participants	56.2 Years STANDARD_DEVIATION 12.24 • n=7 Participants	57.5 Years STANDARD_DEVIATION 12.36 • n=5 Participants
Sex: Female, Male Female	14 Participants n=5 Participants	16 Participants n=7 Participants	30 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	14 Participants n=5 Participants	16 Participants n=7 Participants	30 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	5 Participants n=5 Participants	3 Participants n=7 Participants	8 Participants n=5 Participants
Race (NIH/OMB) White	9 Participants n=5 Participants	12 Participants n=7 Participants	21 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: baseline through end of study, up to 3 years

Population: All Patients on study.

Outcome measures

Outcome measures
Measure	Cohort I: MPA-Alone n=14 Participants Medroxyprogesterone progesterone acetate (MPA) will be administered orally as a single daily dose.	Cohort 2: MPA+IdoCM n=16 Participants Medroxyprogesterone progesterone acetate (MPA) will be administered orally as a single daily dose. Cyclophosphamide will be administered orally as a single daily dose. Methotrexate will be administered twice daily on days 1 and 2 of each week.
Clinical Benefit Rate (CR + PR + SD > 6 Months).	7.1 Percent of Participants Interval 0.2 to 33.9	6.3 Percent of Participants Interval 0.2 to 30.2

SECONDARY outcome

Timeframe: baseline through end of treatment

Population: All patients in the study

To evaluate the toxicity of MPA and MPA + ldoCM in this patient population by the number of patients who have grade 3 or 4 adverse events that are related to treatment.

Outcome measures

Outcome measures
Measure	Cohort I: MPA-Alone n=14 Participants Medroxyprogesterone progesterone acetate (MPA) will be administered orally as a single daily dose.	Cohort 2: MPA+IdoCM n=16 Participants Medroxyprogesterone progesterone acetate (MPA) will be administered orally as a single daily dose. Cyclophosphamide will be administered orally as a single daily dose. Methotrexate will be administered twice daily on days 1 and 2 of each week.
Grade 3 or 4 Adverse Events Related to Treatment	2 participants	2 participants

SECONDARY outcome

Timeframe: baseline through end of treatment

Population: Patients who showed clinical benefit (CR, PR, or SD \> 6 months)

To explore the relationship between MPA trough level and clinical benefit. This is done by seeing if the MPA concentrations remained \> 50 ng/mL after initial dose escalation for those patients who showed clinical benefit. The number shows how many of the patients who showed clinical benefit had MPA concentrations \> 50 ng/mL.

Outcome measures

Outcome measures
Measure	Cohort I: MPA-Alone n=1 Participants Medroxyprogesterone progesterone acetate (MPA) will be administered orally as a single daily dose.	Cohort 2: MPA+IdoCM n=1 Participants Medroxyprogesterone progesterone acetate (MPA) will be administered orally as a single daily dose. Cyclophosphamide will be administered orally as a single daily dose. Methotrexate will be administered twice daily on days 1 and 2 of each week.
MPA Trough Level > 50 ng/mL When Have Clinical Benefit	1 participants	1 participants

SECONDARY outcome

Timeframe: Cycle 1 (Day 10-14) and Cycle 2 (Day 1)

Population: All patients with available data

To explore genetic determinants of MPA bioavailability and trough concentration by showing average MPA levels at cycle 1 (Day 10-14) and cycle 2 (Day 1).

Outcome measures

Outcome measures
Measure	Cohort I: MPA-Alone n=14 Participants Medroxyprogesterone progesterone acetate (MPA) will be administered orally as a single daily dose.	Cohort 2: MPA+IdoCM n=16 Participants Medroxyprogesterone progesterone acetate (MPA) will be administered orally as a single daily dose. Cyclophosphamide will be administered orally as a single daily dose. Methotrexate will be administered twice daily on days 1 and 2 of each week.
MPA Trough Concentration Cycle 1, Day 10-14	14.5 ng/mL Standard Deviation 8.9	42.1 ng/mL Standard Deviation 66.4
MPA Trough Concentration Cycle 2, Day 1	52.6 ng/mL Standard Deviation 65.3	66.4 ng/mL Standard Deviation 71.5

Adverse Events

Cohort 1: MPA Alone

Serious events: 2 serious events

Other events: 14 other events

Deaths: 0 deaths

Cohort 2: MPA+IdoCM

Serious events: 2 serious events

Other events: 12 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Cohort 1: MPA Alone n=14 participants at risk Medroxyprogesterone progesterone acetate (MPA) will be administered orally as a single daily dose.	Cohort 2: MPA+IdoCM n=16 participants at risk Medroxyprogesterone progesterone acetate (MPA) will be administered orally as a single daily dose. Cyclophosphamide will be administered orally as a single daily dose. Methotrexate will be administered twice daily on days 1 and 2 of each week.
Respiratory, thoracic and mediastinal disorders DYSPNEA (SHORTNESS OF BREATH)	0.00% 0/14 • Throughout the entire study, up to 3 years.	12.5% 2/16 • Number of events 2 • Throughout the entire study, up to 3 years.
Metabolism and nutrition disorders DEHYDRATION	0.00% 0/14 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Musculoskeletal and connective tissue disorders FRACTURE	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	0.00% 0/16 • Throughout the entire study, up to 3 years.
Renal and urinary disorders RENAL FAILURE	0.00% 0/14 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Respiratory, thoracic and mediastinal disorders ASPIRATION	0.00% 0/14 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Respiratory, thoracic and mediastinal disorders HYPOXIA	0.00% 0/14 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Respiratory, thoracic and mediastinal disorders PNEUMOTHORAX	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	0.00% 0/16 • Throughout the entire study, up to 3 years.

Other adverse events

Additional Information

Kathy Miller, MD

IndianaU

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Cohort 1: MPA Alone n=14 participants at risk Medroxyprogesterone progesterone acetate (MPA) will be administered orally as a single daily dose.	Cohort 2: MPA+IdoCM n=16 participants at risk Medroxyprogesterone progesterone acetate (MPA) will be administered orally as a single daily dose. Cyclophosphamide will be administered orally as a single daily dose. Methotrexate will be administered twice daily on days 1 and 2 of each week.
Blood and lymphatic system disorders DERMAL CHANGE LYMPHEDEMA, PHLEBOLYMPHEDEMA	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	0.00% 0/16 • Throughout the entire study, up to 3 years.
Blood and lymphatic system disorders LYMPHATICS	0.00% 0/14 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Ear and labyrinth disorders AUDITORY/EAR	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	0.00% 0/16 • Throughout the entire study, up to 3 years.
Gastrointestinal disorders CONSTIPATION	35.7% 5/14 • Number of events 5 • Throughout the entire study, up to 3 years.	25.0% 4/16 • Number of events 4 • Throughout the entire study, up to 3 years.
Gastrointestinal disorders DIARRHEA	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	12.5% 2/16 • Number of events 2 • Throughout the entire study, up to 3 years.
Gastrointestinal disorders DRY MOUTH/SALIVARY GLAND (XEROSTOMIA)	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	0.00% 0/16 • Throughout the entire study, up to 3 years.
Gastrointestinal disorders DYSPHAGIA (DIFFICULTY SWALLOWING)	0.00% 0/14 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Gastrointestinal disorders GASTRITIS (INCLUDING BILE REFLUX GASTRITIS)	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Gastrointestinal disorders GASTROINTESTINAL - OTHER (SPECIFY, __)	0.00% 0/14 • Throughout the entire study, up to 3 years.	12.5% 2/16 • Number of events 2 • Throughout the entire study, up to 3 years.
Gastrointestinal disorders HEARTBURN/DYSPEPSIA	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Gastrointestinal disorders MUCOSITIS/STOMATITIS (CLINICAL EXAM) - STOMACH	0.00% 0/14 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Gastrointestinal disorders MUCOSITIS/STOMATITIS (FUNCTIONAL/SYMPTOMATIC) - ESOPHAGUS	0.00% 0/14 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Gastrointestinal disorders NAUSEA	21.4% 3/14 • Number of events 3 • Throughout the entire study, up to 3 years.	18.8% 3/16 • Number of events 3 • Throughout the entire study, up to 3 years.
Gastrointestinal disorders PAIN - ABDOMEN NOS	0.00% 0/14 • Throughout the entire study, up to 3 years.	12.5% 2/16 • Number of events 2 • Throughout the entire study, up to 3 years.
Gastrointestinal disorders TASTE ALTERATION (DYSGEUSIA)	21.4% 3/14 • Number of events 3 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Gastrointestinal disorders VOMITING	14.3% 2/14 • Number of events 2 • Throughout the entire study, up to 3 years.	0.00% 0/16 • Throughout the entire study, up to 3 years.
General disorders FATIGUE (ASTHENIA, LETHARGY, MALAISE)	50.0% 7/14 • Number of events 7 • Throughout the entire study, up to 3 years.	43.8% 7/16 • Number of events 7 • Throughout the entire study, up to 3 years.
General disorders FEVER (IN THE ABSENCE OF NEUTROPENIA, WHERE NEUTROPENIA IS DEFINED AS ANC <1.0 X 10E9/L)	0.00% 0/14 • Throughout the entire study, up to 3 years.	12.5% 2/16 • Number of events 2 • Throughout the entire study, up to 3 years.
General disorders PAIN - OTHER (SPECIFY, __)	21.4% 3/14 • Number of events 3 • Throughout the entire study, up to 3 years.	18.8% 3/16 • Number of events 3 • Throughout the entire study, up to 3 years.
Infections and infestations INFECTION - OTHER (SPECIFY, __)	0.00% 0/14 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Infections and infestations INFECTION WITH NORMAL ANC OR GRADE 1 OR 2 NEUTROPHILS - BLADDER (URINARY)	0.00% 0/14 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Infections and infestations INFECTION WITH NORMAL ANC OR GRADE 1 OR 2 NEUTROPHILS - LUNG (PNEUMONIA)	0.00% 0/14 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Infections and infestations INFECTION WITH UNKNOWN ANC - NECK NOS	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	0.00% 0/16 • Throughout the entire study, up to 3 years.
Infections and infestations PAIN - SKIN	0.00% 0/14 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Injury, poisoning and procedural complications BURN	0.00% 0/14 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Investigations ALKALINE PHOSPHATASE	0.00% 0/14 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Investigations ALT, SGPT (SERUM GLUTAMIC PYRUVIC TRANSAMINASE)	0.00% 0/14 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Investigations AST, SGOT(SERUM GLUTAMIC OXALOACETIC TRANSAMINASE)	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	0.00% 0/16 • Throughout the entire study, up to 3 years.
Investigations BICARBONATE, SERUM-LOW	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	0.00% 0/16 • Throughout the entire study, up to 3 years.
Investigations HEMOGLOBIN	14.3% 2/14 • Number of events 2 • Throughout the entire study, up to 3 years.	0.00% 0/16 • Throughout the entire study, up to 3 years.
Investigations INR (INTERNATIONAL NORMALIZED RATIO OF PROTHROMBIN TIME)	14.3% 2/14 • Number of events 2 • Throughout the entire study, up to 3 years.	0.00% 0/16 • Throughout the entire study, up to 3 years.
Investigations METABOLIC/LABORATORY - OTHER (SPECIFY, __)	0.00% 0/14 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Investigations PTT (PARTIAL THROMBOPLASTIN TIME)	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	0.00% 0/16 • Throughout the entire study, up to 3 years.
Investigations WEIGHT GAIN	0.00% 0/14 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Metabolism and nutrition disorders ANOREXIA	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Metabolism and nutrition disorders CALCIUM, SERUM-LOW (HYPOCALCEMIA)	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	0.00% 0/16 • Throughout the entire study, up to 3 years.
Metabolism and nutrition disorders POTASSIUM, SERUM-LOW (HYPOKALEMIA)	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	0.00% 0/16 • Throughout the entire study, up to 3 years.
Metabolism and nutrition disorders URIC ACID, SERUM-HIGH (HYPERURICEMIA)	0.00% 0/14 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Musculoskeletal and connective tissue disorders EDEMA: LIMB	21.4% 3/14 • Number of events 3 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Musculoskeletal and connective tissue disorders PAIN - BACK	14.3% 2/14 • Number of events 2 • Throughout the entire study, up to 3 years.	18.8% 3/16 • Number of events 3 • Throughout the entire study, up to 3 years.
Musculoskeletal and connective tissue disorders PAIN - BONE	0.00% 0/14 • Throughout the entire study, up to 3 years.	12.5% 2/16 • Number of events 2 • Throughout the entire study, up to 3 years.
Musculoskeletal and connective tissue disorders PAIN - CHEST WALL	0.00% 0/14 • Throughout the entire study, up to 3 years.	12.5% 2/16 • Number of events 2 • Throughout the entire study, up to 3 years.
Musculoskeletal and connective tissue disorders PAIN - CHEST/THORAX NOS	14.3% 2/14 • Number of events 2 • Throughout the entire study, up to 3 years.	0.00% 0/16 • Throughout the entire study, up to 3 years.
Musculoskeletal and connective tissue disorders PAIN - EXTREMITY-LIMB	14.3% 2/14 • Number of events 2 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Musculoskeletal and connective tissue disorders PAIN - JOINT	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	12.5% 2/16 • Number of events 2 • Throughout the entire study, up to 3 years.
Musculoskeletal and connective tissue disorders PAIN - MUSCLE	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Musculoskeletal and connective tissue disorders PAIN - NECK	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	0.00% 0/16 • Throughout the entire study, up to 3 years.
Musculoskeletal and connective tissue disorders PAIN - PAIN NOS	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	0.00% 0/16 • Throughout the entire study, up to 3 years.
Nervous system disorders ENCEPHALOPATHY	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	0.00% 0/16 • Throughout the entire study, up to 3 years.
Nervous system disorders NEUROLOGY - OTHER (SPECIFY, __)	0.00% 0/14 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Nervous system disorders NEUROPATHY: SENSORY	42.9% 6/14 • Number of events 6 • Throughout the entire study, up to 3 years.	12.5% 2/16 • Number of events 2 • Throughout the entire study, up to 3 years.
Nervous system disorders PAIN - HEAD/HEADACHE	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	12.5% 2/16 • Number of events 2 • Throughout the entire study, up to 3 years.
Nervous system disorders PAIN - NEURALGIA/PERIPHERAL NERVE	0.00% 0/14 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Nervous system disorders SPEECH IMPAIRMENT (E.G., DYSPHASIA OR APHASIA)	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	0.00% 0/16 • Throughout the entire study, up to 3 years.
Nervous system disorders SWEATING (DIAPHORESIS)	14.3% 2/14 • Number of events 2 • Throughout the entire study, up to 3 years.	0.00% 0/16 • Throughout the entire study, up to 3 years.
Nervous system disorders TREMOR	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	0.00% 0/16 • Throughout the entire study, up to 3 years.
Psychiatric disorders INSOMNIA	35.7% 5/14 • Number of events 5 • Throughout the entire study, up to 3 years.	31.2% 5/16 • Number of events 5 • Throughout the entire study, up to 3 years.
Psychiatric disorders MOOD ALTERATION - AGITATION	0.00% 0/14 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Psychiatric disorders MOOD ALTERATION - ANXIETY	28.6% 4/14 • Number of events 4 • Throughout the entire study, up to 3 years.	12.5% 2/16 • Number of events 2 • Throughout the entire study, up to 3 years.
Psychiatric disorders MOOD ALTERATION - DEPRESSION	28.6% 4/14 • Number of events 4 • Throughout the entire study, up to 3 years.	12.5% 2/16 • Number of events 2 • Throughout the entire study, up to 3 years.
Reproductive system and breast disorders HOT FLASHES/FLUSHES	28.6% 4/14 • Number of events 4 • Throughout the entire study, up to 3 years.	12.5% 2/16 • Number of events 2 • Throughout the entire study, up to 3 years.
Reproductive system and breast disorders IRREGULAR MENSES (CHANGE FROM BASELINE)	0.00% 0/14 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Reproductive system and breast disorders MEMORY IMPAIRMENT	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Reproductive system and breast disorders PAIN - BREAST	14.3% 2/14 • Number of events 2 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Reproductive system and breast disorders VAGINAL DRYNESS	0.00% 0/14 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Respiratory, thoracic and mediastinal disorders ALLERGIC RHINITIS (INCLUDING SNEEZING, NASAL STUFFINESS, POSTNASAL DRIP)	0.00% 0/14 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Respiratory, thoracic and mediastinal disorders COUGH	50.0% 7/14 • Number of events 7 • Throughout the entire study, up to 3 years.	31.2% 5/16 • Number of events 5 • Throughout the entire study, up to 3 years.
Respiratory, thoracic and mediastinal disorders DIZZINESS	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	0.00% 0/16 • Throughout the entire study, up to 3 years.
Respiratory, thoracic and mediastinal disorders DYSPNEA (SHORTNESS OF BREATH)	57.1% 8/14 • Number of events 8 • Throughout the entire study, up to 3 years.	43.8% 7/16 • Number of events 7 • Throughout the entire study, up to 3 years.
Respiratory, thoracic and mediastinal disorders HICCOUGHS (HICCUPS, SINGULTUS)	0.00% 0/14 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Respiratory, thoracic and mediastinal disorders NASAL CAVITY/PARANASAL SINUS REACTIONS	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	0.00% 0/16 • Throughout the entire study, up to 3 years.
Respiratory, thoracic and mediastinal disorders VOICE CHANGES/DYSARTHRIA (E.G., HOARSENESS, LOSS OR ALTERATION IN VOICE, LARYNGITIS)	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	12.5% 2/16 • Number of events 2 • Throughout the entire study, up to 3 years.
Skin and subcutaneous tissue disorders ATROPHY, SKIN	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	0.00% 0/16 • Throughout the entire study, up to 3 years.
Skin and subcutaneous tissue disorders DERMATOLOGY/SKIN - OTHER (SPECIFY, __)	14.3% 2/14 • Number of events 2 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Skin and subcutaneous tissue disorders HAIR LOSS/ALOPECIA (SCALP OR BODY)	21.4% 3/14 • Number of events 3 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Skin and subcutaneous tissue disorders MUCOSITIS/STOMATITIS (CLINICAL EXAM) - ORAL CAVITY	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	18.8% 3/16 • Number of events 3 • Throughout the entire study, up to 3 years.
Skin and subcutaneous tissue disorders NAIL CHANGES	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	0.00% 0/16 • Throughout the entire study, up to 3 years.
Skin and subcutaneous tissue disorders PRURITUS/ITCHING	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	6.2% 1/16 • Number of events 1 • Throughout the entire study, up to 3 years.
Skin and subcutaneous tissue disorders RASH/DESQUAMATION	14.3% 2/14 • Number of events 2 • Throughout the entire study, up to 3 years.	18.8% 3/16 • Number of events 3 • Throughout the entire study, up to 3 years.
Skin and subcutaneous tissue disorders ULCERATION	7.1% 1/14 • Number of events 1 • Throughout the entire study, up to 3 years.	0.00% 0/16 • Throughout the entire study, up to 3 years.