Trametinib in Treating Patients With Recurrent or Progressive Low-Grade Ovarian Cancer or Peritoneal Cavity Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02101788
• Collaborator: NRG Oncology (Other)
• Enrollment: 260
• Locations: 508
• Arms: 2
• Patients Per Site: 0.5

Study Details

Study Description

Brief Summary

This phase II/III trial studies how well trametinib works and compares it to standard treatment with either letrozole, tamoxifen, paclitaxel, pegylated liposomal doxorubicin, or topotecan in treating patients with low-grade ovarian cancer or peritoneal cavity cancer that has come back (recurrent), become worse (progressive), or spread to other parts of the body. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether trametinib is more effective than standard therapy in treating patients with ovarian or peritoneal cavity cancer.

Condition or Disease	Intervention/Treatment	Phase
Borderline Ovarian Serous Tumor; Micropapillary Serous Carcinoma; Ovarian Serous Adenocarcinoma; Primary Peritoneal Serous Adenocarcinoma; Recurrent Low Grade Ovarian Serous Adenocarcinoma; Recurrent Primary Peritoneal Serous Adenocarcinoma	Drug: Letrozole; Drug: Paclitaxel; Drug: Pegylated Liposomal Doxorubicin Hydrochloride; Other: Quality-of-Life Assessment; Other: Questionnaire Administration; Drug: Tamoxifen Citrate; Drug: Topotecan; Drug: Trametinib Dimethyl Sulfoxide	Phase 2/Phase 3

Detailed Description

PRIMARY OBJECTIVE:

1. To estimate the progression-free survival (PFS) hazard ratio of trametinib compared to that of "commercially available therapies" consisting of one of five commercially available agents in women with recurrent low-grade serous carcinoma of the ovary or peritoneum previously treated with platinum-based chemotherapy.

SECONDARY OBJECTIVES:

1. To determine the nature, frequency and maximum degree of toxicity as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4 for each treatment arm.

2. To determine the quality of life, as assessed by the Functional Assessment of Cancer Therapy-Ovarian (FACT-O).

IIa. To compare trametinib to the control arm with regard to patients' self-reported acute (up to post-cycle 6) quality of life as measured by the FACT-O-Trial Outcome Index (TOI).

IIb. To compare trametinib to the control arm with regard to patients' self-reported acute (up to post-cycle 6) neurotoxicity as measured by the FACT-Gynecologic Oncology Group (GOG)-Neurotoxicity (NTX).

1. To estimate the objective response rate (RR) of patients in each treatment arm.

2. To test whether high expression of pERK, as quantified by immunohistochemistry (IHC), is associated with better prognosis (RR or PFS) among patients receiving the randomized treatment.

3. To test whether genetic changes associated with MAPK pathway activation (KRAS, NRAS, HRAS, BRAF, MEK, ERBB2 or NF1) are associated with improved prognosis (RR or PFS) among patients receiving the randomized treatment.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive clinician's choice of either letrozole orally (PO) once daily (QD) on days 1-28, tamoxifen citrate PO twice daily (BID) on days 1-28, paclitaxel intravenously (IV) over 1 hour on days 1, 8, and 15, pegylated liposomal doxorubicin hydrochloride (PLD) IV over 1 hour on day 1, or topotecan IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients developing progressive disease may cross over to Arm B.

ARM B: Patients receive trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually for 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 260 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II/III Study to Assess the Efficacy of Trametinib (GSK 1120212) in Patients With Recurrent or Progressive Low-Grade Serous Ovarian Cancer or Peritoneal Cancer
• Actual Study Start Date: Apr 11, 2014
• Actual Primary Completion Date: Apr 4, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm A (letrozole, tamoxifen, paclitaxel, PLD, topotecan) Patients receive clinician's choice of either letrozole PO QD on days 1-28, tamoxifen citrate PO BID on days 1-28, paclitaxel IV over 1 hour on days 1, 8, and 15, pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 1, or topotecan IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients developing progressive disease may cross over to Arm B.	Drug: Letrozole; Given PO; Other Names: CGS 20267 Femara ; Drug: Paclitaxel; Given IV; Other Names: Anzatax Asotax Bristaxol Praxel Taxol Taxol Konzentrat ; Drug: Pegylated Liposomal Doxorubicin Hydrochloride; Given IV; Other Names: ATI-0918 Caelyx Dox-SL Doxil Doxilen Doxorubicin HCl Liposomal Doxorubicin HCl Liposome Doxorubicin Hydrochloride Liposome Duomeisu Evacet LipoDox Lipodox 50 Liposomal Adriamycin Liposomal Doxorubicin Hydrochloride Liposomal-Encapsulated Doxorubicin Pegylated Doxorubicin HCl Liposome S-Liposomal Doxorubicin Stealth Liposomal Doxorubicin TLC D-99 ; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment ; Other: Questionnaire Administration; Ancillary studies; Drug: Tamoxifen Citrate; Given PO; Other Names: Apo-Tamox Clonoxifen Dignotamoxi Ebefen Emblon Estroxyn Fentamox Gen-Tamoxifen Genox ICI 46,474 ICI-46474 Jenoxifen Kessar Ledertam Lesporene Nolgen Noltam Nolvadex Nolvadex-D Nourytam Novo-Tamoxifen Novofen Noxitem Oestrifen Oncotam PMS-Tamoxifen Soltamox TAM Tamax Tamaxin Tamifen Tamizam Tamofen Tamoxasta Tamoxifeni Citras Zemide ; Drug: Topotecan; Given IV; Other Names: Hycamptamine Topotecan Lactone
Experimental: Arm B (trametinib) Patients receive trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment ; Drug: Trametinib Dimethyl Sulfoxide; Given PO; Other Names: Mekinist

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival (PFS) [Time from study entry to time of progression or death, an average of 7 months for arm A and 13 months for arm B]

   Progression free survival (PFS) was defined as the number of months between study enrollment and documentation of disease progression (RECIST 1.1) or death from any cause. Patients still alive and disease free at the last followup were censored on the date of last CT Scan.Participants were analyzed based on their group of assignment. Patients on Arm A who progressed were permitted to receive Arm B treatment. Study time for Arm A patients who crossed over was not included in the PFS endpoint definition.

Secondary Outcome Measures

1. Incidence of Adverse Events (AEs) [During treatment period and up to 100 days after stopping the study treatment]

   Number of treated patients with Adverse Events (grade 3 or higher) observed while receiving randomized therapy. Excludes AEs observed among control patients treated with trametinib after crossover.Participants were analyzed based on their group of assignment. Patients on Arm A who progressed were permitted to receive Arm B treatment. Study time for Arm A patients who crossed over was not included in the AE endpoint definition.

2. Overall Survival [Time from study entry to time of death or date of last contact, an average of 29 months for arm A and 37 months for arm B]

   Overall survival (OS) was defined as the number of months between study enrollment and death from any cause. Patients still alive at the last follow-up were censored on the date of last contact. Patients with disease progression on the Control arm were allowed to cross over to the trametinib arm. Per the protocol, the intent-to-treat OS analysis was not adjusted for crossover.

3. Objective Tumor Response Rate (Complete Response and Partial Response) [Time from study entry to time of progression or death, an average of 7 months for arm A and 13 months for arm B]

   The Response Rates were estimated as the binomial proportion of patients with Best Overall Response of Complete or Partial response according to RECIST 1.1 criteria.

4. Patients Reported Acute Quality of Life [1. baseline (prior to cycle 1), 12 weeks (prior to cycle 4), 24 weeks (4 weeks post cycle 6), 36 weeks post cycle 1, 52 weeks post cycle 1.]

   Patient reported quality of life was measured with the Treatment Outcome Index (TOI) of the Functional Assessment of Cancer Therapy for ovarian cancer (FACT-O TOI). The FACT-O TOI is a scale for assessing general QOL of ovarian cancer patients. It consists of three subscales: Physical Well Being (7 items), Functional Well Being (7 items), and Ovarian Cancer subscale (11 items). . The FACT-O TOI score is calculated as the sum of the subscale scores if more than 80% of the FACT-O TOI items provide valid answers and all of the component subscales have valid scores. The FACT-O TOI score ranges 0-100 with a large score suggesting better QOL. Participants were analyzed based on their group of assignment. Patients on Arm A who progressed were permitted to receive Arm B treatment. Study time for Arm A patients who crossed over was not included in the quality of life endpoint definition

5. Patient Reported Acute Peripheral Neuropathy Symptoms [Up to 52 weeks]

   Patient reported peripheral neuropathy symptoms was measured with the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - neurotoxicity subscale (short version) (FACT/GOG-Ntx subscale). The FACT/GOG-Ntx subscale contains 4 items. Each item was scored using a 5-point scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). According to the FACIT measurement system, the Ntx score was the summation of the individual item scores if more than 50% of subscale items were answered. When unanswered items existed, a subscale score was prorated by multiplying the mean of the answered item scores by the number of items in the scale. The Ntx score ranges 0-16 with a large score suggesting less peripheral neuropathy symptoms

6. Progression Free Survival [Time from study entry to time of progression or death, an average of 7 months for SOC and 13 months for the treatment (Trametinib) arm.]

   Progression free survival (PFS) was defined as the number of months between study enrollment and documentation of disease progression (RECIST 1.1) or death from any cause. Patients still alive and disease free at the last followup were censored on the date of last CT Scan. RECIST v1.1 defines progression as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.

7. pERK Expression [Baseline]

   Will be quantified using the H-score derived from the immunohistochemistry analysis of patient tumor tissue and is expected to present as a continuous measure. will consider the prognostic and predictive abilities of pERK relative to objective response rate (ORR) or PFS. Analysis of the dichotomous markers will be supported by Kaplan Meier plots, and forest plots of the odds-ratio and hazard ratio estimates. Duration of response will be depicted using swimmer plots, with median duration estimated using Kaplan Meier methods. The multivariable models will include covariate adjustment for geographic region, performance status and number of prior regimens, presented using effect coding. The adjusted hazard- and odds- ratio estimates from the multivariable models will be supported by nominal p-values and 2-sided, 95% confidence intervals. Confidence intervals will be interpreted as the plausible range of values for the true (unobserved) ratio that is supported by the data.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients with the following tumors are included in the study:

• Patients initially diagnosed with low-grade serous ovarian or peritoneal carcinoma that recur as low-grade serous carcinoma (invasive micropapillary serous carcinoma or invasive grade I serous carcinomas as defined by GOG, Federation of Obstetricians and Gynecologists [FIGO], World Health Organization [WHO] or Silverberg)

• Patients initially diagnosed with serous borderline ovarian or peritoneal carcinoma that recur as low-grade serous carcinoma (invasive micropapillary serous carcinoma or invasive grade I serous carcinomas as defined by GOG, FIGO WHO or Silverberg)

• At least 4 weeks must have elapsed since the patient underwent any major surgery (e.g. MAJOR: laparotomy, laparoscopy, thoracotomy, VATS [video assisted thorascopic surgery]); there is no restriction on MINOR procedures: (e.g. central venous catheter placement, ureteral stent placement or exchange, tumor core or fine-needle aspirate [FNA] biopsy)

• Patients must have documented low-grade serous carcinoma; confirmation must occur by prospective pathology review prior to study entry; the prospective pathology review can be done on tissue from the recurrent carcinoma or from original diagnostic specimen

• All patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; measurable disease is defined as at least one target lesion that can be accurately measured in at least one dimension (longest diameter to be recorded); each lesion must be >= 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI), or caliper measurement by clinical exam; or >= 20 mm when measured by chest x-ray; lymph nodes must be >= 15 mm in short axis when measured by CT or MRI; all imaging studies must be performed within 28 days prior to registration

• Prior therapy

• Patients must have recurred or progressed following at least one platinum-based chemotherapy regimen

• Patients may have received an unlimited number of prior therapy regimens

• Patients may not have received all of the five choices in the "standard therapy" arm

• Any hormonal therapy directed at the malignant tumor must be discontinued at least one week prior to registration

• Any other prior therapy directed at the malignant tumor, including chemotherapy and radiation therapy, must be discontinued at least 4 weeks prior to registration; any investigational agent must be discontinued at least 28 days prior to registration

• Trametinib, can cause fetal harm when administered to a pregnant woman; women of child-bearing potential (i.e. patients whose reproductive organs remain in place and who have not passed menopause) and men must agree to use a highly effective method of contraception (e.g. hormonal, intrauterine device or; abstinence*) prior to study entry, during the study participation, and for six months after the last dose of the drug; women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to randomization, cannot be breast-feeding, and must agree to use a highly effective form of contraception throughout the treatment period and for 6 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

• Abstinence is only acceptable when this is in line with the preferred and usual lifestyle of the patient

• Patients must have the ability to understand and sign an approved informed consent and authorization permitting release of personal health information

• Patients must have a GOG performance status of 0 or 1

• Able to swallow and retain orally-administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption, such as malabsorption syndrome, bowel obstruction, or major resection of the stomach or bowel

• All prior treatment-related toxicities must be CTCAE v4 grade =< 1 (except alopecia) at the time of randomization

• Patients must have a left ventricular ejection fraction >= lower limit of normal by echocardiogram (ECHO) or multigated acquisition scan (MUGA)

• Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min (within 14 days prior to treatment)

• Bilirubin =< 1.5 times upper limit of normal (within 14 days prior to treatment)

• Alanine aminotransferase (ALT) =< 2.5 times upper limit of normal (within 14 days prior to treatment)

• Aspartate aminotransferase (AST) =< 2.5 times upper limit of normal (within 14 days prior to treatment)

• Albumin >= 2.5 g/dL (within 14 days prior to treatment)

• Prothrombin time (PT) and activated partial thromboplastin time (APTT) =< 1.5 times upper limit of normal (within 14 days prior to treatment)

• Neutrophil count >= 1.5 x 10^9/L (within 14 days prior to treatment)

• Platelet count >= 100 x 10^9/L (within 14 days prior to treatment)

• Hemoglobin >= 9.0 g/dL (within 14 days prior to treatment)

• If letrozole is selected as the control therapy, patients must be postmenopausal, either following bilateral oophorectomy or at least 5 years after spontaneous menopause; patients within 5 years of spontaneous menopause or who have had a hysterectomy without bilateral oophorectomy must have postmenopausal luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels; patients on hormone replacement therapy (HRT) must agree to withdrawal of hormone therapy before letrozole is started

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier

• Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of trametinib or standard of care agent

• If patients have had a potential index lesion radiated, it must have progressed post radiation therapy to be used as a measurable eligibility lesion

• Patients may not have received prior MEK, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), or v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor therapy

• Current use of a prohibited medication; the following medications or non-drug therapies are prohibited:

• Patients may not be receiving any other anti-cancer or investigational agents

• Because the composition, PK, and metabolism of many herbal supplements are unknown, the concurrent use of all herbal supplements is prohibited during the study (including, but not limited to St. John's wort, kava, ephedra [ma huang], gingko biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng)

• Patients with known leptomeningeal or brain metastases or spinal cord compression should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events

• Patients with a bowel obstruction or any other gastrointestinal condition that might affect absorption of the oral drug should be excluded; this would include patients with inability to swallow and retain orally-administered medication, malabsorption syndrome, or those with a major resection of the stomach or bowels

• Patients with a history of interstitial lung disease or pneumonitis

• Patients with a previous or current malignancy at other sites should be excluded, with the exception of:

• Curatively treated local tumors such as carcinoma-in-situ of the cervix, basal or squamous cell carcinoma of the skin

• Tumors for which no relapse has been observed within 5 years

• Known hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (patients with chronic or cleared HBV and HCV infection are eligible); patients with human immunodeficiency virus (HIV) are not eligible if on anti-retroviral medications

• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib, or excipients, or to dimethyl sulfoxide (DMSO), or to Cremophor EL (polyoxyethylated castor oil); please note, exclusion for Cremophor is unnecessary unless paclitaxel is the only agent available and the patient randomizes to the conventional therapy option

• Patients with a history or evidence of cardiovascular risk, including any of the following:

• Left ventricular ejection fraction (LVEF) < lower limit of normal (LLN)

• Bazett's corrected QT (QTcB) >= 480 msec

• History or evidence of current clinically significant uncontrolled arrhythmias

• Exception: Subjects with controlled atrial fibrillation for > 30 days prior to randomization are eligible

• History of (within 6 months prior to randomization) acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting

• History or evidence of current >= class II congestive heart failure as defined by New York Heart Association (NYHA)

• Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy

• Patients with intra-cardiac defibrillators or permanent pacemakers

• Known cardiac metastases

• Patients with a history or current evidence/risk of retinal vein occlusion (RVO)

• Any serious and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures

• Patients who require use of a concomitant medication that can prolong the QT interval

• Animal reproductive studies have not been conducted with trametinib; therefore, the study drug must not be administered to pregnant women or nursing mothers; women of childbearing potential should be advised to avoid pregnancy and use effective methods of contraception; if a female patient or a female partner of a patient becomes pregnant while the patient receives trametinib, the potential hazard to the fetus should be explained to the patient and partner (as applicable)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Tennessee Valley Gynecologic Oncology	Huntsville	Alabama	United States	35805
2	Anchorage Associates in Radiation Medicine	Anchorage	Alaska	United States	98508
3	Anchorage Radiation Therapy Center	Anchorage	Alaska	United States	99504
4	Alaska Breast Care and Surgery LLC	Anchorage	Alaska	United States	99508
5	Alaska Oncology and Hematology LLC	Anchorage	Alaska	United States	99508
6	Alaska Women's Cancer Care	Anchorage	Alaska	United States	99508
7	Anchorage Oncology Centre	Anchorage	Alaska	United States	99508
8	Katmai Oncology Group	Anchorage	Alaska	United States	99508
9	Providence Alaska Medical Center	Anchorage	Alaska	United States	99508
10	Fairbanks Memorial Hospital	Fairbanks	Alaska	United States	99701
11	Banner University Medical Center - Tucson	Tucson	Arizona	United States	85719
12	University of Arizona Cancer Center-North Campus	Tucson	Arizona	United States	85719
13	CHI Saint Vincent Cancer Center Hot Springs	Hot Springs	Arkansas	United States	71913
14	Sutter Auburn Faith Hospital	Auburn	California	United States	95602
15	Sutter Cancer Centers Radiation Oncology Services-Auburn	Auburn	California	United States	95603
16	Alta Bates Summit Medical Center-Herrick Campus	Berkeley	California	United States	94704
17	Providence Saint Joseph Medical Center/Disney Family Cancer Center	Burbank	California	United States	91505
18	Mills-Peninsula Medical Center	Burlingame	California	United States	94010
19	Sutter Cancer Centers Radiation Oncology Services-Cameron Park	Cameron Park	California	United States	95682
20	Eden Hospital Medical Center	Castro Valley	California	United States	94546
21	Community Cancer Institute	Clovis	California	United States	93611
22	University Oncology Associates	Clovis	California	United States	93611
23	Sutter Davis Hospital	Davis	California	United States	95616
24	Palo Alto Medical Foundation-Fremont	Fremont	California	United States	94538
25	Memorial Medical Center	Modesto	California	United States	95355
26	Palo Alto Medical Foundation-Camino Division	Mountain View	California	United States	94040
27	Palo Alto Medical Foundation-Gynecologic Oncology	Mountain View	California	United States	94040
28	Sutter Cancer Research Consortium	Novato	California	United States	94945
29	Palo Alto Medical Foundation Health Care	Palo Alto	California	United States	94301
30	Stanford Cancer Institute Palo Alto	Palo Alto	California	United States	94304
31	Sutter Cancer Centers Radiation Oncology Services-Roseville	Roseville	California	United States	95661
32	Sutter Roseville Medical Center	Roseville	California	United States	95661
33	Sutter Medical Center Sacramento	Sacramento	California	United States	95816
34	California Pacific Medical Center-Pacific Campus	San Francisco	California	United States	94115
35	UCSF Medical Center-Mission Bay	San Francisco	California	United States	94158
36	Stanford Cancer Center South Bay	San Jose	California	United States	95124
37	Palo Alto Medical Foundation-Santa Cruz	Santa Cruz	California	United States	95065
38	Sutter Pacific Medical Foundation	Santa Rosa	California	United States	95403
39	Palo Alto Medical Foundation-Sunnyvale	Sunnyvale	California	United States	94086
40	Sutter Cancer Centers Radiation Oncology Services-Vacaville	Vacaville	California	United States	95687
41	Sutter Solano Medical Center/Cancer Center	Vallejo	California	United States	94589
42	Rocky Mountain Cancer Centers-Aurora	Aurora	Colorado	United States	80012
43	The Medical Center of Aurora	Aurora	Colorado	United States	80012
44	Boulder Community Hospital	Boulder	Colorado	United States	80301
45	Rocky Mountain Cancer Centers-Boulder	Boulder	Colorado	United States	80304
46	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado	United States	80907
47	Rocky Mountain Cancer Centers-Penrose	Colorado Springs	Colorado	United States	80907
48	Denver Health Medical Center	Denver	Colorado	United States	80204
49	National Jewish Health-Main Campus	Denver	Colorado	United States	80206
50	The Women's Imaging Center	Denver	Colorado	United States	80209
51	Porter Adventist Hospital	Denver	Colorado	United States	80210
52	Colorado Blood Cancer Institute	Denver	Colorado	United States	80218
53	Presbyterian - Saint Lukes Medical Center - Health One	Denver	Colorado	United States	80218
54	Rocky Mountain Cancer Centers-Midtown	Denver	Colorado	United States	80218
55	SCL Health Saint Joseph Hospital	Denver	Colorado	United States	80218
56	Rocky Mountain Cancer Centers-Rose	Denver	Colorado	United States	80220
57	Rose Medical Center	Denver	Colorado	United States	80220
58	Western States Cancer Research NCORP	Denver	Colorado	United States	80222
59	Mercy Medical Center	Durango	Colorado	United States	81301
60	Southwest Oncology PC	Durango	Colorado	United States	81301
61	Mountain Blue Cancer Care Center - Swedish	Englewood	Colorado	United States	80113
62	Swedish Medical Center	Englewood	Colorado	United States	80113
63	Mountain Blue Cancer Care Center	Golden	Colorado	United States	80401
64	National Jewish Health-Western Hematology Oncology	Golden	Colorado	United States	80401
65	North Colorado Medical Center	Greeley	Colorado	United States	80631
66	Rocky Mountain Cancer Centers-Greenwood Village	Greenwood Village	Colorado	United States	80111
67	Rocky Mountain Cancer Centers-Lakewood	Lakewood	Colorado	United States	80228
68	Saint Anthony Hospital	Lakewood	Colorado	United States	80228
69	Rocky Mountain Cancer Centers-Littleton	Littleton	Colorado	United States	80120
70	Littleton Adventist Hospital	Littleton	Colorado	United States	80122
71	Rocky Mountain Cancer Centers-Sky Ridge	Lone Tree	Colorado	United States	80124
72	Sky Ridge Medical Center	Lone Tree	Colorado	United States	80124
73	Longmont United Hospital	Longmont	Colorado	United States	80501
74	Rocky Mountain Cancer Centers-Longmont	Longmont	Colorado	United States	80501
75	McKee Medical Center	Loveland	Colorado	United States	80539
76	Parker Adventist Hospital	Parker	Colorado	United States	80138
77	Rocky Mountain Cancer Centers-Parker	Parker	Colorado	United States	80138
78	Saint Mary Corwin Medical Center	Pueblo	Colorado	United States	81004
79	Rocky Mountain Cancer Centers - Pueblo	Pueblo	Colorado	United States	81008
80	National Jewish Health-Northern Hematology Oncology	Thornton	Colorado	United States	80260
81	Rocky Mountain Cancer Centers-Thornton	Thornton	Colorado	United States	80260
82	SCL Health Lutheran Medical Center	Wheat Ridge	Colorado	United States	80033
83	Hartford Hospital	Hartford	Connecticut	United States	06102
84	Smilow Cancer Hospital Care Center at Saint Francis	Hartford	Connecticut	United States	06105
85	The Hospital of Central Connecticut	New Britain	Connecticut	United States	06050
86	Sibley Memorial Hospital	Washington	District of Columbia	United States	20016
87	UM Sylvester Comprehensive Cancer Center at Coral Gables	Coral Gables	Florida	United States	33146
88	UM Sylvester Comprehensive Cancer Center at Deerfield Beach	Deerfield Beach	Florida	United States	33442
89	Jackson Memorial Hospital-Holtz Children's Hospital	Miami	Florida	United States	33136
90	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida	United States	33136
91	UM Sylvester Comprehensive Cancer Center at Plantation	Plantation	Florida	United States	33324
92	Northside Hospital	Atlanta	Georgia	United States	30342
93	John B Amos Cancer Center	Columbus	Georgia	United States	31904
94	Northside Hospital-Forsyth	Cumming	Georgia	United States	30041
95	Northeast Georgia Medical Center-Gainesville	Gainesville	Georgia	United States	30501
96	Lewis Cancer and Research Pavilion at Saint Joseph's/Candler	Savannah	Georgia	United States	31405
97	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho	United States	83706
98	Saint Luke's Cancer Institute - Boise	Boise	Idaho	United States	83712
99	Saint Alphonsus Cancer Care Center-Caldwell	Caldwell	Idaho	United States	83605
100	Kootenai Health - Coeur d'Alene	Coeur d'Alene	Idaho	United States	83814
101	Walter Knox Memorial Hospital	Emmett	Idaho	United States	83617
102	Saint Luke's Cancer Institute - Fruitland	Fruitland	Idaho	United States	83619
103	Idaho Urologic Institute-Meridian	Meridian	Idaho	United States	83642
104	Saint Luke's Cancer Institute - Meridian	Meridian	Idaho	United States	83642
105	Saint Alphonsus Medical Center-Nampa	Nampa	Idaho	United States	83686
106	Saint Luke's Cancer Institute - Nampa	Nampa	Idaho	United States	83686
107	Kootenai Clinic Cancer Services - Post Falls	Post Falls	Idaho	United States	83854
108	Kootenai Cancer Clinic	Sandpoint	Idaho	United States	83864
109	Saint Luke's Cancer Institute - Twin Falls	Twin Falls	Idaho	United States	83301
110	Rush - Copley Medical Center	Aurora	Illinois	United States	60504
111	Northwestern University	Chicago	Illinois	United States	60611
112	Swedish Covenant Hospital	Chicago	Illinois	United States	60625
113	Carle on Vermilion	Danville	Illinois	United States	61832
114	Carle Physician Group-Effingham	Effingham	Illinois	United States	62401
115	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois	United States	60201
116	Saint Francis Hospital	Evanston	Illinois	United States	60202
117	Northwestern Medicine Cancer Center Delnor	Geneva	Illinois	United States	60134
118	NorthShore University HealthSystem-Glenbrook Hospital	Glenview	Illinois	United States	60026
119	NorthShore University HealthSystem-Highland Park Hospital	Highland Park	Illinois	United States	60035
120	Sudarshan K Sharma MD Limited-Gynecologic Oncology	Hinsdale	Illinois	United States	60521
121	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois	United States	61938
122	Good Samaritan Regional Health Center	Mount Vernon	Illinois	United States	62864
123	North Shore Medical Center	Skokie	Illinois	United States	60076
124	Carle Cancer Center	Urbana	Illinois	United States	61801
125	The Carle Foundation Hospital	Urbana	Illinois	United States	61801
126	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois	United States	60555
127	Rush-Copley Healthcare Center	Yorkville	Illinois	United States	60560
128	Michiana Hematology Oncology PC-Crown Point	Crown Point	Indiana	United States	46307
129	Elkhart Clinic	Elkhart	Indiana	United States	46514-2098
130	Michiana Hematology Oncology PC-Elkhart	Elkhart	Indiana	United States	46514
131	Elkhart General Hospital	Elkhart	Indiana	United States	46515
132	Deaconess Clinic Downtown	Evansville	Indiana	United States	47713
133	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
134	Saint Vincent Hospital and Health Care Center	Indianapolis	Indiana	United States	46260
135	Community Howard Regional Health	Kokomo	Indiana	United States	46904
136	IU Health La Porte Hospital	La Porte	Indiana	United States	46350
137	Franciscan Saint Anthony Health-Michigan City	Michigan City	Indiana	United States	46360
138	Woodland Cancer Care Center	Michigan City	Indiana	United States	46360
139	Memorial Regional Cancer Center Day Road	Mishawaka	Indiana	United States	46545
140	Michiana Hematology Oncology PC-Mishawaka	Mishawaka	Indiana	United States	46545
141	Saint Joseph Regional Medical Center-Mishawaka	Mishawaka	Indiana	United States	46545
142	Chancellor Center for Oncology	Newburgh	Indiana	United States	47630
143	Michiana Hematology Oncology PC-Plymouth	Plymouth	Indiana	United States	46563
144	Memorial Hospital of South Bend	South Bend	Indiana	United States	46601
145	Michiana Hematology Oncology PC-South Bend	South Bend	Indiana	United States	46601
146	South Bend Clinic	South Bend	Indiana	United States	46617
147	Northern Indiana Cancer Research Consortium	South Bend	Indiana	United States	46628
148	Michiana Hematology Oncology PC-Westville	Westville	Indiana	United States	46391
149	Medical Oncology and Hematology Associates-West Des Moines	Clive	Iowa	United States	50325
150	Mercy Cancer Center-West Lakes	Clive	Iowa	United States	50325
151	Alegent Health Mercy Hospital	Council Bluffs	Iowa	United States	51503
152	Greater Regional Medical Center	Creston	Iowa	United States	50801
153	Iowa Methodist Medical Center	Des Moines	Iowa	United States	50309
154	Medical Oncology and Hematology Associates-Des Moines	Des Moines	Iowa	United States	50309
155	Broadlawns Medical Center	Des Moines	Iowa	United States	50314
156	Medical Oncology and Hematology Associates-Laurel	Des Moines	Iowa	United States	50314
157	Mercy Medical Center - Des Moines	Des Moines	Iowa	United States	50314
158	Iowa Lutheran Hospital	Des Moines	Iowa	United States	50316
159	Methodist West Hospital	West Des Moines	Iowa	United States	50266-7700
160	Mercy Medical Center-West Lakes	West Des Moines	Iowa	United States	50266
161	Flaget Memorial Hospital	Bardstown	Kentucky	United States	40004
162	Commonwealth Cancer Center-Corbin	Corbin	Kentucky	United States	40701
163	Saint Joseph Radiation Oncology Resource Center	Lexington	Kentucky	United States	40504
164	Saint Joseph Hospital East	Lexington	Kentucky	United States	40509
165	Saint Joseph London	London	Kentucky	United States	40741
166	Jewish Hospital	Louisville	Kentucky	United States	40202
167	The James Graham Brown Cancer Center at University of Louisville	Louisville	Kentucky	United States	40202
168	Saints Mary and Elizabeth Hospital	Louisville	Kentucky	United States	40215
169	Jewish Hospital Medical Center Northeast	Louisville	Kentucky	United States	40245
170	Jewish Hospital Medical Center South	Shepherdsville	Kentucky	United States	40165
171	Woman's Hospital	Baton Rouge	Louisiana	United States	70817
172	Maine Medical Center- Scarborough Campus	Scarborough	Maine	United States	04074
173	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
174	Walter Reed National Military Medical Center	Bethesda	Maryland	United States	20889-5600
175	Baystate Medical Center	Springfield	Massachusetts	United States	01199
176	Saint Joseph Mercy Hospital	Ann Arbor	Michigan	United States	48106
177	Bronson Battle Creek	Battle Creek	Michigan	United States	49017
178	IHA Hematology Oncology Consultants-Brighton	Brighton	Michigan	United States	48114
179	Saint Joseph Mercy Brighton	Brighton	Michigan	United States	48114
180	IHA Hematology Oncology Consultants-Canton	Canton	Michigan	United States	48188
181	Saint Joseph Mercy Canton	Canton	Michigan	United States	48188
182	Caro Cancer Center	Caro	Michigan	United States	48723
183	IHA Hematology Oncology Consultants-Chelsea	Chelsea	Michigan	United States	48118
184	Saint Joseph Mercy Chelsea	Chelsea	Michigan	United States	48118
185	Hematology Oncology Consultants-Clarkston	Clarkston	Michigan	United States	48346
186	Newland Medical Associates-Clarkston	Clarkston	Michigan	United States	48346
187	Beaumont Hospital - Dearborn	Dearborn	Michigan	United States	48124
188	Ascension Saint John Hospital	Detroit	Michigan	United States	48236
189	Great Lakes Cancer Management Specialists-Doctors Park	East China Township	Michigan	United States	48054
190	Genesee Cancer and Blood Disease Treatment Center	Flint	Michigan	United States	48503
191	Genesee Hematology Oncology PC	Flint	Michigan	United States	48503
192	Genesys Hurley Cancer Institute	Flint	Michigan	United States	48503
193	Hurley Medical Center	Flint	Michigan	United States	48503
194	Mercy Health Saint Mary's	Grand Rapids	Michigan	United States	49503
195	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan	United States	49503
196	Academic Hematology Oncology Specialists	Grosse Pointe Woods	Michigan	United States	48236
197	Great Lakes Cancer Management Specialists-Van Elslander Cancer Center	Grosse Pointe Woods	Michigan	United States	48236
198	Michigan Breast Specialists-Grosse Pointe Woods	Grosse Pointe Woods	Michigan	United States	48236
199	Allegiance Health	Jackson	Michigan	United States	49201
200	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007
201	Borgess Medical Center	Kalamazoo	Michigan	United States	49048
202	Sparrow Hospital	Lansing	Michigan	United States	48912
203	Hope Cancer Clinic	Livonia	Michigan	United States	48154
204	Saint Mary Mercy Hospital	Livonia	Michigan	United States	48154
205	Great Lakes Cancer Management Specialists-Macomb Medical Campus	Macomb	Michigan	United States	48044
206	Michigan Breast Specialists-Macomb Township	Macomb	Michigan	United States	48044
207	Saint Mary's Oncology/Hematology Associates of Marlette	Marlette	Michigan	United States	48453
208	Monroe Cancer Center	Monroe	Michigan	United States	48162
209	Mercy Health Mercy Campus	Muskegon	Michigan	United States	49444
210	Lakeland Hospital Niles	Niles	Michigan	United States	49120
211	21st Century Oncology-Pontiac	Pontiac	Michigan	United States	48341
212	Hope Cancer Center	Pontiac	Michigan	United States	48341
213	Newland Medical Associates-Pontiac	Pontiac	Michigan	United States	48341
214	Saint Joseph Mercy Oakland	Pontiac	Michigan	United States	48341
215	Lake Huron Medical Center	Port Huron	Michigan	United States	48060
216	Spectrum Health Reed City Hospital	Reed City	Michigan	United States	49677
217	Great Lakes Cancer Management Specialists-Rochester Hills	Rochester Hills	Michigan	United States	48309
218	Ascension Saint Mary's Hospital	Saginaw	Michigan	United States	48601
219	Oncology Hematology Associates of Saginaw Valley PC	Saginaw	Michigan	United States	48604
220	Lakeland Medical Center Saint Joseph	Saint Joseph	Michigan	United States	49085
221	Marie Yeager Cancer Center	Saint Joseph	Michigan	United States	49085
222	Bhadresh Nayak MD PC-Sterling Heights	Sterling Heights	Michigan	United States	48312
223	Ascension Saint Joseph Hospital	Tawas City	Michigan	United States	48764
224	Munson Medical Center	Traverse City	Michigan	United States	49684
225	Advanced Breast Care Center PLLC	Warren	Michigan	United States	48088
226	Great Lakes Cancer Management Specialists-Macomb Professional Building	Warren	Michigan	United States	48093
227	Macomb Hematology Oncology PC	Warren	Michigan	United States	48093
228	Michigan Breast Specialists-Warren	Warren	Michigan	United States	48093
229	Saint John Macomb-Oakland Hospital	Warren	Michigan	United States	48093
230	Saint Mary's Oncology/Hematology Associates of West Branch	West Branch	Michigan	United States	48661
231	Metro Health Hospital	Wyoming	Michigan	United States	49519
232	Huron Gastroenterology PC	Ypsilanti	Michigan	United States	48106
233	IHA Hematology Oncology Consultants-Ann Arbor	Ypsilanti	Michigan	United States	48197
234	Sanford Joe Lueken Cancer Center	Bemidji	Minnesota	United States	56601
235	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
236	Central Care Cancer Center - Bolivar	Bolivar	Missouri	United States	65613
237	Cox Cancer Center Branson	Branson	Missouri	United States	65616
238	Freeman Health System	Joplin	Missouri	United States	64804
239	Mercy Hospital Joplin	Joplin	Missouri	United States	64804
240	Delbert Day Cancer Institute at PCRMC	Rolla	Missouri	United States	65401
241	Mercy Clinic-Rolla-Cancer and Hematology	Rolla	Missouri	United States	65401
242	Heartland Regional Medical Center	Saint Joseph	Missouri	United States	64506
243	Saint Louis Cancer and Breast Institute-South City	Saint Louis	Missouri	United States	63109
244	Barnes-Jewish Hospital	Saint Louis	Missouri	United States	63110
245	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
246	Mercy Hospital Saint Louis	Saint Louis	Missouri	United States	63141
247	Mercy Hospital Springfield	Springfield	Missouri	United States	65804
248	CoxHealth South Hospital	Springfield	Missouri	United States	65807
249	Community Hospital of Anaconda	Anaconda	Montana	United States	59711
250	Billings Clinic Cancer Center	Billings	Montana	United States	59101
251	Saint Vincent Healthcare	Billings	Montana	United States	59101
252	Bozeman Deaconess Hospital	Bozeman	Montana	United States	59715
253	Saint James Community Hospital and Cancer Treatment Center	Butte	Montana	United States	59701
254	Benefis Healthcare- Sletten Cancer Institute	Great Falls	Montana	United States	59405
255	Great Falls Clinic	Great Falls	Montana	United States	59405
256	Saint Peter's Community Hospital	Helena	Montana	United States	59601
257	Kalispell Regional Medical Center	Kalispell	Montana	United States	59901
258	Saint Patrick Hospital - Community Hospital	Missoula	Montana	United States	59802
259	Community Medical Hospital	Missoula	Montana	United States	59804
260	CHI Health Saint Francis	Grand Island	Nebraska	United States	68803
261	Heartland Hematology and Oncology	Kearney	Nebraska	United States	68845
262	CHI Health Good Samaritan	Kearney	Nebraska	United States	68847
263	Saint Elizabeth Regional Medical Center	Lincoln	Nebraska	United States	68510
264	Nebraska Methodist Hospital	Omaha	Nebraska	United States	68114
265	Alegent Health Immanuel Medical Center	Omaha	Nebraska	United States	68122
266	Hematology and Oncology Consultants PC	Omaha	Nebraska	United States	68122
267	Alegent Health Bergan Mercy Medical Center	Omaha	Nebraska	United States	68124
268	Alegent Health Lakeside Hospital	Omaha	Nebraska	United States	68130
269	Creighton University Medical Center	Omaha	Nebraska	United States	68131
270	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
271	Midlands Community Hospital	Papillion	Nebraska	United States	68046
272	Women's Cancer Center of Nevada	Las Vegas	Nevada	United States	89169
273	Center of Hope at Renown Medical Center	Reno	Nevada	United States	89502
274	Renown Regional Medical Center	Reno	Nevada	United States	89502
275	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
276	Cooper Hospital University Medical Center	Camden	New Jersey	United States	08103
277	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
278	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey	United States	08903
279	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08903
280	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87102
281	New Mexico Cancer Care Alliance	Albuquerque	New Mexico	United States	87106
282	Southwest Gynecologic Oncology Associates Inc	Albuquerque	New Mexico	United States	87106
283	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
284	NYP/Weill Cornell Medical Center	New York	New York	United States	10065
285	University of Rochester	Rochester	New York	United States	14642
286	Dickstein Cancer Treatment Center	White Plains	New York	United States	10601
287	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599
288	Novant Health Presbyterian Medical Center	Charlotte	North Carolina	United States	28204
289	Oncology Specialists of Charlotte	Charlotte	North Carolina	United States	28207
290	Southern Oncology Specialists-Charlotte	Charlotte	North Carolina	United States	28262
291	Sampson Radiation Oncology	Clinton	North Carolina	United States	28328
292	Southeastern Medical Oncology Center-Clinton	Clinton	North Carolina	United States	28328
293	Duke University Medical Center	Durham	North Carolina	United States	27710
294	Southeastern Medical Oncology Center-Goldsboro	Goldsboro	North Carolina	United States	27534
295	Wayne Memorial Hospital	Goldsboro	North Carolina	United States	27534
296	Wayne Radiation Oncology	Goldsboro	North Carolina	United States	27534
297	Novant Health Cancer Institute - Huntersville	Huntersville	North Carolina	United States	28078
298	Southern Oncology Specialists-Huntersville	Huntersville	North Carolina	United States	28078
299	Onslow Memorial Hospital	Jacksonville	North Carolina	United States	28546
300	Southeastern Medical Oncology Center-Jacksonville	Jacksonville	North Carolina	United States	28546
301	Matthews Radiation Oncology Center	Matthews	North Carolina	United States	28105
302	Novant Health Cancer Specialists-Matthews	Matthews	North Carolina	United States	28105
303	Novant Health Cancer Institute - Mooresville	Mooresville	North Carolina	United States	28117
304	Duke Women's Cancer Care Raleigh	Raleigh	North Carolina	United States	27607
305	Duke Raleigh Hospital	Raleigh	North Carolina	United States	27609
306	Sanford Bismarck Medical Center	Bismarck	North Dakota	United States	58501
307	Sanford Broadway Medical Center	Fargo	North Dakota	United States	58122
308	Sanford Clinic North-Fargo	Fargo	North Dakota	United States	58122
309	Sanford Roger Maris Cancer Center	Fargo	North Dakota	United States	58122
310	UHHS-Chagrin Highlands Medical Center	Beachwood	Ohio	United States	44122
311	Strecker Cancer Center-Belpre	Belpre	Ohio	United States	45714
312	Adena Regional Medical Center	Chillicothe	Ohio	United States	45601
313	University of Cincinnati/Barrett Cancer Center	Cincinnati	Ohio	United States	45219
314	Good Samaritan Hospital - Cincinnati	Cincinnati	Ohio	United States	45220
315	Bethesda North Hospital	Cincinnati	Ohio	United States	45242
316	TriHealth Cancer Institute-Westside	Cincinnati	Ohio	United States	45247
317	TriHealth Cancer Institute-Anderson	Cincinnati	Ohio	United States	45255
318	Case Western Reserve University	Cleveland	Ohio	United States	44106
319	MetroHealth Medical Center	Cleveland	Ohio	United States	44109
320	Cleveland Clinic Cancer Center/Fairview Hospital	Cleveland	Ohio	United States	44111
321	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
322	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
323	Columbus Oncology and Hematology Associates Inc	Columbus	Ohio	United States	43214
324	Riverside Methodist Hospital	Columbus	Ohio	United States	43214
325	Columbus NCI Community Oncology Research Program	Columbus	Ohio	United States	43215
326	Grant Medical Center	Columbus	Ohio	United States	43215
327	The Mark H Zangmeister Center	Columbus	Ohio	United States	43219
328	Mount Carmel Health Center West	Columbus	Ohio	United States	43222
329	Doctors Hospital	Columbus	Ohio	United States	43228
330	Grandview Hospital	Dayton	Ohio	United States	45405
331	Delaware Health Center-Grady Cancer Center	Delaware	Ohio	United States	43015
332	Delaware Radiation Oncology	Delaware	Ohio	United States	43015
333	Grady Memorial Hospital	Delaware	Ohio	United States	43015
334	Fairfield Medical Center	Lancaster	Ohio	United States	43130
335	Lancaster Radiation Oncology	Lancaster	Ohio	United States	43130
336	Marietta Memorial Hospital	Marietta	Ohio	United States	45750
337	Hillcrest Hospital Cancer Center	Mayfield Heights	Ohio	United States	44124
338	UH Seidman Cancer Center at Landerbrook Health Center	Mayfield Heights	Ohio	United States	44124
339	UH Seidman Cancer Center at Lake Health Mentor Campus	Mentor	Ohio	United States	44060
340	Knox Community Hospital	Mount Vernon	Ohio	United States	43050
341	Licking Memorial Hospital	Newark	Ohio	United States	43055
342	Newark Radiation Oncology	Newark	Ohio	United States	43055
343	Southern Ohio Medical Center	Portsmouth	Ohio	United States	45662
344	Springfield Regional Medical Center	Springfield	Ohio	United States	45505
345	ProMedica Flower Hospital	Sylvania	Ohio	United States	43560
346	ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital	Toledo	Ohio	United States	43606
347	University Hospitals Sharon Health Center	Wadsworth	Ohio	United States	44281
348	Saint Ann's Hospital	Westerville	Ohio	United States	43081
349	UHHS-Westlake Medical Center	Westlake	Ohio	United States	44145
350	Genesis Healthcare System Cancer Care Center	Zanesville	Ohio	United States	43701
351	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
352	Mercy Hospital Oklahoma City	Oklahoma City	Oklahoma	United States	73120
353	Oklahoma Cancer Specialists and Research Institute-Tulsa	Tulsa	Oklahoma	United States	74146
354	Saint Alphonsus Medical Center-Baker City	Baker City	Oregon	United States	97814
355	Saint Charles Health System	Bend	Oregon	United States	97701
356	Clackamas Radiation Oncology Center	Clackamas	Oregon	United States	97015
357	Providence Cancer Institute Clackamas Clinic	Clackamas	Oregon	United States	97015
358	Bay Area Hospital	Coos Bay	Oregon	United States	97420
359	Legacy Mount Hood Medical Center	Gresham	Oregon	United States	97030
360	Providence Newberg Medical Center	Newberg	Oregon	United States	97132
361	Saint Alphonsus Medical Center-Ontario	Ontario	Oregon	United States	97914
362	Providence Willamette Falls Medical Center	Oregon City	Oregon	United States	97045
363	Legacy Good Samaritan Hospital and Medical Center	Portland	Oregon	United States	97210
364	Providence Portland Medical Center	Portland	Oregon	United States	97213
365	Providence Saint Vincent Medical Center	Portland	Oregon	United States	97225
366	Abington Memorial Hospital	Abington	Pennsylvania	United States	19001
367	Lehigh Valley Hospital-Cedar Crest	Allentown	Pennsylvania	United States	18103
368	Saint Luke's University Hospital-Bethlehem Campus	Bethlehem	Pennsylvania	United States	18015
369	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania	United States	18017
370	Geisinger Medical Center	Danville	Pennsylvania	United States	17822
371	Easton Hospital	Easton	Pennsylvania	United States	18042
372	Geisinger Medical Center-Cancer Center Hazleton	Hazleton	Pennsylvania	United States	18201
373	Armstrong Center for Medicine and Health	Kittanning	Pennsylvania	United States	16201
374	Geisinger Medical Oncology-Lewisburg	Lewisburg	Pennsylvania	United States	17837
375	Lewistown Hospital	Lewistown	Pennsylvania	United States	17044
376	University of Pennsylvania/Abramson Cancer Center	Philadelphia	Pennsylvania	United States	19104
377	West Penn Hospital	Pittsburgh	Pennsylvania	United States	15224
378	Geisinger Cancer Services-Pottsville	Pottsville	Pennsylvania	United States	17901
379	Geisinger Medical Group	State College	Pennsylvania	United States	16801
380	Chester County Hospital	West Chester	Pennsylvania	United States	19380
381	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania	United States	18711
382	Women and Infants Hospital	Providence	Rhode Island	United States	02905
383	Gibbs Cancer Center-Gaffney	Gaffney	South Carolina	United States	29341
384	Saint Francis Hospital	Greenville	South Carolina	United States	29601
385	Saint Francis Cancer Center	Greenville	South Carolina	United States	29607
386	Gibbs Cancer Center-Pelham	Greer	South Carolina	United States	29651
387	Spartanburg Medical Center	Spartanburg	South Carolina	United States	29303
388	MGC Hematology Oncology-Union	Union	South Carolina	United States	29379
389	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota	United States	57104
390	Avera Cancer Institute	Sioux Falls	South Dakota	United States	57105
391	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota	United States	57117-5134
392	Memorial Hospital	Chattanooga	Tennessee	United States	37404
393	Pulmonary Medicine Center of Chattanooga-Hixson	Hixson	Tennessee	United States	37343
394	Memorial GYN Plus	Ooltewah	Tennessee	United States	37363
395	Saint Joseph Regional Cancer Center	Bryan	Texas	United States	77802
396	MD Anderson in The Woodlands	Conroe	Texas	United States	77384
397	Parkland Memorial Hospital	Dallas	Texas	United States	75235
398	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
399	Houston Methodist Hospital	Houston	Texas	United States	77030
400	M D Anderson Cancer Center	Houston	Texas	United States	77030
401	Memorial Hermann Texas Medical Center	Houston	Texas	United States	77030
402	MD Anderson West Houston	Houston	Texas	United States	77079
403	MD Anderson League City	League City	Texas	United States	77573
404	MD Anderson in Sugar Land	Sugar Land	Texas	United States	77478
405	Houston Methodist Sugar Land Hospital	Sugar Land	Texas	United States	77479
406	American Fork Hospital / Huntsman Intermountain Cancer Center	American Fork	Utah	United States	84003
407	Sandra L Maxwell Cancer Center	Cedar City	Utah	United States	84720
408	Logan Regional Hospital	Logan	Utah	United States	84321
409	Intermountain Medical Center	Murray	Utah	United States	84107
410	McKay-Dee Hospital Center	Ogden	Utah	United States	84403
411	Utah Valley Regional Medical Center	Provo	Utah	United States	84604
412	Dixie Medical Center Regional Cancer Center	Saint George	Utah	United States	84770
413	Utah Cancer Specialists-Salt Lake City	Salt Lake City	Utah	United States	84106
414	LDS Hospital	Salt Lake City	Utah	United States	84143
415	Providence Regional Cancer System-Aberdeen	Aberdeen	Washington	United States	98520
416	Cancer Care Center at Island Hospital	Anacortes	Washington	United States	98221
417	MultiCare Auburn Medical Center	Auburn	Washington	United States	98001
418	Virginia Mason Bainbridge Island Medical Center	Bainbridge Island	Washington	United States	98110
419	Overlake Medical Center	Bellevue	Washington	United States	98004
420	Swedish Cancer Institute-Eastside Oncology Hematology	Bellevue	Washington	United States	98005
421	PeaceHealth Saint Joseph Medical Center	Bellingham	Washington	United States	98225
422	Harrison HealthPartners Hematology and Oncology-Bremerton	Bremerton	Washington	United States	98310
423	Harrison Medical Center	Bremerton	Washington	United States	98310
424	Highline Medical Center-Main Campus	Burien	Washington	United States	98166
425	Providence Regional Cancer System-Centralia	Centralia	Washington	United States	98531
426	Swedish Cancer Institute-Edmonds	Edmonds	Washington	United States	98026
427	Saint Elizabeth Hospital	Enumclaw	Washington	United States	98022
428	Providence Regional Cancer Partnership	Everett	Washington	United States	98201
429	Virginia Mason Federal Way Medical Center	Federal Way	Washington	United States	98002
430	Saint Francis Hospital	Federal Way	Washington	United States	98003
431	Tacoma/Valley Radiation Oncology Centers-Gig Harbor	Gig Harbor	Washington	United States	98332
432	MultiCare Gig Harbor Medical Park	Gig Harbor	Washington	United States	98335
433	Swedish Cancer Institute-Issaquah	Issaquah	Washington	United States	98029
434	Kadlec Clinic Hematology and Oncology	Kennewick	Washington	United States	99336
435	Northwest Cancer Clinic	Kennewick	Washington	United States	99336
436	Providence Regional Cancer System-Lacey	Lacey	Washington	United States	98503
437	Saint Clare Hospital	Lakewood	Washington	United States	98499
438	PeaceHealth Saint John Medical Center	Longview	Washington	United States	98632
439	Virginia Mason Lynnwood Medical Center	Lynnwood	Washington	United States	98036
440	Jefferson Healthcare	Port Townsend	Washington	United States	98368
441	Harrison HealthPartners Hematology and Oncology-Poulsbo	Poulsbo	Washington	United States	98370
442	Peninsula Cancer Center	Poulsbo	Washington	United States	98370
443	MultiCare Good Samaritan Hospital	Puyallup	Washington	United States	98372
444	Tacoma/Valley Radiation Oncology Centers-Puyallup	Puyallup	Washington	United States	98372
445	Virginia Mason Medical Center	Seattle	Washington	United States	98101
446	Minor and James Medical PLLC	Seattle	Washington	United States	98104
447	Pacific Gynecology Specialists	Seattle	Washington	United States	98104
448	Swedish Medical Center-Ballard Campus	Seattle	Washington	United States	98107
449	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109
450	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
451	Kaiser Permanente Washington	Seattle	Washington	United States	98112
452	Swedish Medical Center-First Hill	Seattle	Washington	United States	98122-4307
453	Swedish Medical Center-Cherry Hill	Seattle	Washington	United States	98122-5711
454	University of Washington Medical Center - Northwest	Seattle	Washington	United States	98133
455	Women's Cancer Center of Seattle	Seattle	Washington	United States	98133
456	University of Washington Medical Center - Montlake	Seattle	Washington	United States	98195
457	Providence Regional Cancer System-Shelton	Shelton	Washington	United States	98584
458	MultiCare Deaconess Cancer and Blood Specialty Center - Valley	Spokane Valley	Washington	United States	99216
459	MultiCare Deaconess Cancer and Blood Specialty Center - Downtown	Spokane	Washington	United States	99204
460	MultiCare Deaconess Cancer and Blood Specialty Center - North	Spokane	Washington	United States	99218
461	Tacoma/Valley Radiation Oncology Centers-Jackson Hall	Tacoma	Washington	United States	97405
462	Franciscan Research Center-Northwest Medical Plaza	Tacoma	Washington	United States	98405
463	MultiCare Tacoma General Hospital	Tacoma	Washington	United States	98405
464	Northwest Medical Specialties PLLC	Tacoma	Washington	United States	98405
465	Northwest NCI Community Oncology Research Program	Tacoma	Washington	United States	98405
466	Tacoma/Valley Radiation Oncology Centers-Saint Joe's	Tacoma	Washington	United States	98405
467	PeaceHealth Southwest Medical Center	Vancouver	Washington	United States	98664
468	Legacy Salmon Creek Hospital	Vancouver	Washington	United States	98686
469	Providence Saint Mary Regional Cancer Center	Walla Walla	Washington	United States	99362
470	North Star Lodge Cancer Center at Yakima Valley Memorial Hospital	Yakima	Washington	United States	98902
471	Providence Regional Cancer System-Yelm	Yelm	Washington	United States	98597
472	Aurora Cancer Care-Southern Lakes VLCC	Burlington	Wisconsin	United States	53105
473	Aurora Health Center-Fond du Lac	Fond Du Lac	Wisconsin	United States	54937
474	Aurora Health Care Germantown Health Center	Germantown	Wisconsin	United States	53022
475	Aurora Cancer Care-Grafton	Grafton	Wisconsin	United States	53024
476	Aurora BayCare Medical Center	Green Bay	Wisconsin	United States	54311
477	Mercyhealth Hospital and Cancer Center - Janesville	Janesville	Wisconsin	United States	53548
478	Aurora Cancer Care-Kenosha South	Kenosha	Wisconsin	United States	53142
479	Aurora Bay Area Medical Group-Marinette	Marinette	Wisconsin	United States	54143
480	Aurora Cancer Care-Milwaukee	Milwaukee	Wisconsin	United States	53209
481	Aurora Saint Luke's Medical Center	Milwaukee	Wisconsin	United States	53215
482	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
483	Aurora Sinai Medical Center	Milwaukee	Wisconsin	United States	53233
484	Vince Lombardi Cancer Clinic - Oshkosh	Oshkosh	Wisconsin	United States	54904
485	Aurora Cancer Care-Racine	Racine	Wisconsin	United States	53406
486	Vince Lombardi Cancer Clinic-Sheboygan	Sheboygan	Wisconsin	United States	53081
487	Aurora Medical Center in Summit	Summit	Wisconsin	United States	53066
488	Vince Lombardi Cancer Clinic-Two Rivers	Two Rivers	Wisconsin	United States	54241
489	Aurora Cancer Care-Waukesha	Waukesha	Wisconsin	United States	53188
490	Aurora Cancer Care-Milwaukee West	Wauwatosa	Wisconsin	United States	53226
491	Aurora West Allis Medical Center	West Allis	Wisconsin	United States	53227
492	Cheyenne Regional Medical Center-West	Cheyenne	Wyoming	United States	82001
493	Big Horn Basin Cancer Center	Cody	Wyoming	United States	82414
494	Billings Clinic-Cody	Cody	Wyoming	United States	82414
495	Welch Cancer Center	Sheridan	Wyoming	United States	82801
496	Bristol Royal Infirmary	Bristol	England	United Kingdom	BS2 8ED
497	Addenbrookes Hospital-Medical School	Cambridge	England	United Kingdom	CB2 0QQ
498	Saint Bartholomew's Hospital	London	England	United Kingdom	EC1A 7BE
499	Hammersmith Hospital	London	England	United Kingdom	W12 0HS
500	University College London Hospital	London	England	United Kingdom	WC1E 6AG
501	Christie Hospital	Manchester	England	United Kingdom	M20 4BX
502	Musgrove Park Hospital	Somerset	England	United Kingdom	TA1 5DA
503	Saint James's University Hospital	West Yorkshire	England	United Kingdom	LS9 7TF
504	Belfast City Hospital	Belfast	Northern Ireland	United Kingdom	BT9 7AB
505	Western General Hospital	Edinburgh	Scotland	United Kingdom	EH4 2XU
506	Beatson Oncology Center	Glasgow	Scotland	United Kingdom	G12 0YN
507	The Royal Marsden NHS Foundation Trust-Chelsea	London		United Kingdom	SW3 6JJ
508	Nottingham City Hospital	Nottingham		United Kingdom	NG5 1PB

Sponsors and Collaborators

• National Cancer Institute (NCI)
• NRG Oncology

Investigators

• Principal Investigator: David M Gershenson, NRG Oncology

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 24, 2020

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT02101788
• Other Study ID Numbers: NCI-2014-00629; NCI-2014-00629; GOG-0281; GOG-0281; P50CA083639; U10CA180868
• First Posted: Apr 2, 2014
• Last Update Posted: Jan 12, 2022
• Last Verified: Dec 1, 2021

• Additional relevant MeSH terms: Adenocarcinoma; Cystadenocarcinoma, Serous; Recurrence; Tamoxifen; Paclitaxel; Doxorubicin; Liposomal doxorubicin; Albumin-Bound Paclitaxel; Letrozole; Topotecan; Trametinib; Dimethyl Sulfoxide

Study Results

Participant Flow

Recruitment Details	A total of 260 patients enrolled before accrual closed on 04/10/2018.

Arm/Group Title	Arm A - Control Arm	Arm B - Experimental Arm
Arm/Group Description	Investigators choice of Letrozole 2.5 mg po qd continuously, tamoxifen 20mg po bid continuously, paclitaxel 80mg/m2 IV over 1 hr on day 1q 7d, 3 wks on, 1 wk off, Pegylated Liposomal Doxorubicin 40 or 50mg/m2 IV over 1 hr on day 1 q. 28d, Topotecan 4.0mg/m2 over 30 min on day 1,8 and 15 of a 28 day cycle. For each arm, 1 cycle - 28 days	Trametinib 2 mg po daily continuous treatment, For each arm, 1 cycle = 28 days
Period Title: Overall Study
STARTED	130	130
Crossover From Arm A to Arm B	88	0
COMPLETED	120	116
NOT COMPLETED	10	14

Baseline Characteristics

Arm/Group Title	Arm A - Control Arm	Arm B - Experimental Arm	Total
Arm/Group Description	Investigators choice of Letrozole 2.5 mg po qd continuously, tamoxifen 20mg po bid continuously, paclitaxel 80mg/m2 IV over 1 hr on day 1q 7d, 3 wks on, 1 wk off, Pegylated Liposomal Doxorubicin 40 or 50mg/m2 IV over 1 hr on day 1 q. 28d, Topotecan 4.0mg/m2 over 30 min on day 1,8 and 15 of a 28 day cycle. For each arm, 1 cycle - 28 days	Trametinib 2 mg po daily continuous treatment, For each arm, 1 cycle = 28 days	Total of all reporting groups
Overall Participants	130	130	260
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.89 (14.03)	53.57 (14.13)	53.7 (14.1)
Age, Customized (Count of Participants)
20-29 years	9 6.9%	10 7.7%	19 7.3%
30-39 years	18 13.8%	16 12.3%	34 13.1%
40-49 years	21 16.2%	22 16.9%	43 16.5%
50-59 years	28 21.5%	35 26.9%	63 24.2%
60-69 years	39 30%	33 25.4%	72 27.7%
>= 70 years	15 11.5%	14 10.8%	29 11.2%
Sex: Female, Male (Count of Participants)
Female	130 100%	130 100%	260 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	7 5.4%	8 6.2%	15 5.8%
Not Hispanic or Latino	118 90.8%	118 90.8%	236 90.8%
Unknown or Not Reported	5 3.8%	4 3.1%	9 3.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 1.5%	2 1.5%	4 1.5%
Native Hawaiian or Other Pacific Islander	2 1.5%	2 1.5%	4 1.5%
Black or African American	5 3.8%	4 3.1%	9 3.5%
White	114 87.7%	115 88.5%	229 88.1%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	7 5.4%	7 5.4%	14 5.4%
Region of Enrollment (participants) [Number]
United States	102 78.5%	103 79.2%	205 78.8%
United Kingdom	28 21.5%	27 20.8%	55 21.2%
Number of Prior Treatment Regimens (Count of Participants)
1 Prior Treatment Regimens	30 23.1%	29 22.3%	59 22.7%
2 Prior Treatment Regimens	37 28.5%	39 30%	76 29.2%
3 or More Prior Treatment Regimens	63 48.5%	62 47.7%	125 48.1%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS)
Description	Progression free survival (PFS) was defined as the number of months between study enrollment and documentation of disease progression (RECIST 1.1) or death from any cause. Patients still alive and disease free at the last followup were censored on the date of last CT Scan.Participants were analyzed based on their group of assignment. Patients on Arm A who progressed were permitted to receive Arm B treatment. Study time for Arm A patients who crossed over was not included in the PFS endpoint definition.
Time Frame	Time from study entry to time of progression or death, an average of 7 months for arm A and 13 months for arm B

Outcome Measure Data

Analysis Population Description

All randomized patients

Arm/Group Title	Arm A - Control Arm	Arm B - Experimental Arm
Arm/Group Description	Investigators choice of Letrozole 2.5 mg po qd continuously, tamoxifen 20mg po bid continuously, paclitaxel 80mg/m2 IV over 1 hr on day 1q 7d, 3 wks on, 1 wk off, Pegylated Liposomal Doxorubicin 40 or 50mg/m2 IV over 1 hr on day 1 q. 28d, Topotecan 4.0mg/m2 over 30 min on day 1,8 and 15 of a 28 day cycle. For each arm, 1 cycle - 28 days	Trametinib 2 mg po daily continuous treatment, For each arm, 1 cycle = 28 days
Measure Participants	130	130
Median (95% Confidence Interval) [months]	7.2	13.0

2. Secondary Outcome

Title	Incidence of Adverse Events (AEs)
Description	Number of treated patients with Adverse Events (grade 3 or higher) observed while receiving randomized therapy. Excludes AEs observed among control patients treated with trametinib after crossover.Participants were analyzed based on their group of assignment. Patients on Arm A who progressed were permitted to receive Arm B treatment. Study time for Arm A patients who crossed over was not included in the AE endpoint definition.
Time Frame	During treatment period and up to 100 days after stopping the study treatment

Outcome Measure Data

Analysis Population Description

Treated with randomized therapy

Arm/Group Title	Arm A - Control Arm	Arm B - Experimental Arm
Arm/Group Description	Investigators choice of Letrozole 2.5 mg po qd continuously, tamoxifen 20mg po bid continuously, paclitaxel 80mg/m2 IV over 1 hr on day 1q 7d, 3 wks on, 1 wk off, Pegylated Liposomal Doxorubicin 40 or 50mg/m2 IV over 1 hr on day 1 q. 28d, Topotecan 4.0mg/m2 over 30 min on day 1,8 and 15 of a 28 day cycle. For each arm, 1 cycle - 28 days	Trametinib 2 mg po daily continuous treatment, For each arm, 1 cycle = 28 days
Measure Participants	127	127
Abdominal pain	22 16.9%	7 5.4%
Anemia	12 9.2%	16 12.3%
Diarrhea	4 3.1%	13 10%
Fatigue	5 3.8%	10 7.7%
Hypertension	6 4.6%	15 11.5%
Nausea	14 10.8%	12 9.2%
Neutrophil count decreased	1 0.8%	8 6.2%
Rash maculo-papular	0 0%	9 6.9%
Small Intestinal Obstruction	9 6.9%	16 12.3%
Vomiting	10 7.7%	9 6.9%

3. Secondary Outcome

Title	Overall Survival
Description	Overall survival (OS) was defined as the number of months between study enrollment and death from any cause. Patients still alive at the last follow-up were censored on the date of last contact. Patients with disease progression on the Control arm were allowed to cross over to the trametinib arm. Per the protocol, the intent-to-treat OS analysis was not adjusted for crossover.
Time Frame	Time from study entry to time of death or date of last contact, an average of 29 months for arm A and 37 months for arm B

Outcome Measure Data

Analysis Population Description

All randomized patients

Arm/Group Title	Arm A - Control Arm	Arm B - Experimental Arm
Arm/Group Description	Investigators choice of Letrozole 2.5 mg po qd continuously, tamoxifen 20mg po bid continuously, paclitaxel 80mg/m2 IV over 1 hr on day 1q 7d, 3 wks on, 1 wk off, Pegylated Liposomal Doxorubicin 40 or 50mg/m2 IV over 1 hr on day 1 q. 28d, Topotecan 4.0mg/m2 over 30 min on day 1,8 and 15 of a 28 day cycle. For each arm, 1 cycle - 28 days	Trametinib 2 mg po daily continuous treatment, For each arm, 1 cycle = 28 days
Measure Participants	130	130
Median (95% Confidence Interval) [Months]	29.2	37.0

4. Secondary Outcome

Title	Objective Tumor Response Rate (Complete Response and Partial Response)
Description	The Response Rates were estimated as the binomial proportion of patients with Best Overall Response of Complete or Partial response according to RECIST 1.1 criteria.
Time Frame	Time from study entry to time of progression or death, an average of 7 months for arm A and 13 months for arm B

Outcome Measure Data

Analysis Population Description

Randomized patients

Arm/Group Title	Arm A - Control Arm	Arm B - Experimental Arm
Arm/Group Description	Investigators choice of Letrozole 2.5 mg po qd continuously, tamoxifen 20mg po bid continuously, paclitaxel 80mg/m2 IV over 1 hr on day 1q 7d, 3 wks on, 1 wk off, Pegylated Liposomal Doxorubicin 40 or 50mg/m2 IV over 1 hr on day 1 q. 28d, Topotecan 4.0mg/m2 over 30 min on day 1,8 and 15 of a 28 day cycle. For each arm, 1 cycle - 28 days	Trametinib 2 mg po daily continuous treatment, For each arm, 1 cycle = 28 days
Measure Participants	130	130
Number [participants]	8 6.2%	34 26.2%

5. Secondary Outcome

Title	Patients Reported Acute Quality of Life
Description	Patient reported quality of life was measured with the Treatment Outcome Index (TOI) of the Functional Assessment of Cancer Therapy for ovarian cancer (FACT-O TOI). The FACT-O TOI is a scale for assessing general QOL of ovarian cancer patients. It consists of three subscales: Physical Well Being (7 items), Functional Well Being (7 items), and Ovarian Cancer subscale (11 items). . The FACT-O TOI score is calculated as the sum of the subscale scores if more than 80% of the FACT-O TOI items provide valid answers and all of the component subscales have valid scores. The FACT-O TOI score ranges 0-100 with a large score suggesting better QOL. Participants were analyzed based on their group of assignment. Patients on Arm A who progressed were permitted to receive Arm B treatment. Study time for Arm A patients who crossed over was not included in the quality of life endpoint definition
Time Frame	1. baseline (prior to cycle 1), 12 weeks (prior to cycle 4), 24 weeks (4 weeks post cycle 6), 36 weeks post cycle 1, 52 weeks post cycle 1.

Outcome Measure Data

Analysis Population Description

Patients who provided baseline and ≥ 1 follow-up assessment

Arm/Group Title	Arm A (Letrozole, Tamoxifen, Paclitaxel, PLD, Topotecan)	Arm B (Trametinib)
Arm/Group Description	Patients receive clinician's choice of either letrozole PO QD on days 1-28, tamoxifen citrate PO BID on days 1-28, paclitaxel IV over 1 hour on days 1, 8, and 15, pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 1, or topotecan hydrochloride IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients developing progressive disease may cross over to Arm B. Letrozole: Given PO Paclitaxel: Given IV Pegylated Liposomal Doxorubicin Hydrochloride: Given IV Quality-of-Life Assessment: Ancillary studies Tamoxifen: Given PO Tamoxifen Citrate: Given PO Topotecan: Given IV Topotecan Hydrochloride: Given IV	Patients receive trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Quality-of-Life Assessment: Ancillary studies Trametinib: Given PO Trametinib Dimethyl Sulfoxide: Given PO
Measure Participants	98	100
Baseline	74.5 (16.6)	74.5 (13.7)
12 Weeks	74.2 (16.0)	70.6 (13.5)
24 Weeks	70.2 (15.5)	73.0 (12.8)
36 Weeks	69.3 (18.6)	72.6 (12.8)
52 Weeks	72.1 (16.9)	73.3 (14.3)

6. Secondary Outcome

Title	Patient Reported Acute Peripheral Neuropathy Symptoms
Description	Patient reported peripheral neuropathy symptoms was measured with the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - neurotoxicity subscale (short version) (FACT/GOG-Ntx subscale). The FACT/GOG-Ntx subscale contains 4 items. Each item was scored using a 5-point scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). According to the FACIT measurement system, the Ntx score was the summation of the individual item scores if more than 50% of subscale items were answered. When unanswered items existed, a subscale score was prorated by multiplying the mean of the answered item scores by the number of items in the scale. The Ntx score ranges 0-16 with a large score suggesting less peripheral neuropathy symptoms
Time Frame	Up to 52 weeks

Outcome Measure Data

Analysis Population Description

Patients that provided baseline and ≥ 1 follow-up assessment

Arm/Group Title	Arm A (Letrozole, Tamoxifen, Paclitaxel, PLD, Topotecan)	Arm B (Trametinib)
Arm/Group Description	Patients receive clinician's choice of either letrozole PO QD on days 1-28, tamoxifen citrate PO BID on days 1-28, paclitaxel IV over 1 hour on days 1, 8, and 15, pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 1, or topotecan hydrochloride IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients developing progressive disease may cross over to Arm B. Letrozole: Given PO Paclitaxel: Given IV Pegylated Liposomal Doxorubicin Hydrochloride: Given IV Quality-of-Life Assessment: Ancillary studies Tamoxifen: Given PO Tamoxifen Citrate: Given PO Topotecan: Given IV Topotecan Hydrochloride: Given IV	Patients receive trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Quality-of-Life Assessment: Ancillary studies Trametinib: Given PO Trametinib Dimethyl Sulfoxide: Given PO
Measure Participants	98	100
Baseline	13.2 (3.5)	12.8 (3.8)
12 Weeks	12.5 (4.0)	12.6 (4.2)
24 Weeks	12.4 (4.0)	12.1 (4.2)
36 Weeks	12.3 (3.8)	12.6 (3.9)
52 Weeks	12.8 (3.2)	12.4 (4.2)

7. Secondary Outcome

Title	Progression Free Survival
Description	Progression free survival (PFS) was defined as the number of months between study enrollment and documentation of disease progression (RECIST 1.1) or death from any cause. Patients still alive and disease free at the last followup were censored on the date of last CT Scan. RECIST v1.1 defines progression as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.
Time Frame	Time from study entry to time of progression or death, an average of 7 months for SOC and 13 months for the treatment (Trametinib) arm.

Outcome Measure Data

Analysis Population Description

Patients with sufficient tissue for analysis

Arm/Group Title	KRAS/BRAF/NRAS Mutant Group (MAPK Pathway) (Trametinib)	KRAS/BRAF/NRAS Mutant Group (MAPK Pathway) (SOC)	KRAS/BRAF/NRAS Wild-type (MAPK Pathway) (Trametinib)	KRAS/BRAF/NRAS Wild-type (MAPK Pathway) (SOC)
Arm/Group Description	KRAS/BRAF/NRAS mutant group (MAPK pathway) (Trametinib treatment) - Whole Exome Sequencing	KRAS/BRAF/NRAS mutant group (MAPK pathway) (Standard of Care treatment) - Whole Exome Sequencing	KRAS/BRAF/NRAS wild-type (MAPK pathway) (Trametinib treatment) - Whole Exome Sequencing	KRAS/BRAF/NRAS wild-type (MAPK pathway) (Standard of Care treatment) - Whole Exome Sequencing
Measure Participants	22	22	48	42
Median (95% Confidence Interval) [Months]	13.2	11.4	7.3	6.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A - Control Arm, Arm B - Experimental Arm
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.55
	Confidence Interval	(2-Sided) 95%; 0.28 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimation of treatment effect; Trametinib vs. SOC among patients with a mutation.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KRAS/BRAF/NRAS Wild-type (MAPK Pathway) (Trametinib), KRAS/BRAF/NRAS Wild-type (MAPK Pathway) (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 95%; 0.39 to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimation of treatment effect; Trametinib vs. SOC among wild-type patients.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Arm B - Experimental Arm, KRAS/BRAF/NRAS Wild-type (MAPK Pathway) (SOC)
	Comments	Prognostic effect of the mutation status among patients in the SOC arm.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0929
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.60
	Confidence Interval	(2-Sided) 95%; 0.34 to 1.08
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimation of mutation effect; mutant vs. wild-type in the SOC group.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Arm A - Control Arm, Arm B - Experimental Arm, KRAS/BRAF/NRAS Wild-type (MAPK Pathway) (Trametinib), KRAS/BRAF/NRAS Wild-type (MAPK Pathway) (SOC)
	Comments	Predictive effect biomarker p-value
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7195
	Comments
	Method	Chi-squared
	Comments

8. Secondary Outcome

Title	pERK Expression
Description	Will be quantified using the H-score derived from the immunohistochemistry analysis of patient tumor tissue and is expected to present as a continuous measure. will consider the prognostic and predictive abilities of pERK relative to objective response rate (ORR) or PFS. Analysis of the dichotomous markers will be supported by Kaplan Meier plots, and forest plots of the odds-ratio and hazard ratio estimates. Duration of response will be depicted using swimmer plots, with median duration estimated using Kaplan Meier methods. The multivariable models will include covariate adjustment for geographic region, performance status and number of prior regimens, presented using effect coding. The adjusted hazard- and odds- ratio estimates from the multivariable models will be supported by nominal p-values and 2-sided, 95% confidence intervals. Confidence intervals will be interpreted as the plausible range of values for the true (unobserved) ratio that is supported by the data.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Starting with the first treatment received, and ending 100 days after the last treatment, or at the last following, whichever is sooner. Time frame was approximately 30 months.
Arm/Group Title	Arm A - Control Arm		Arm B - Experimental Arm		Crossover From Control to Experimental Arm
Arm/Group Description	Investigators choice of Letrozole 2.5 mg po qd continuously, tamoxifen 20mg po bid continuously, paclitaxel 80mg/m2 IV over 1 hr on day 1q 7d, 3 wks on, 1 wk off, Pegylated Liposomal Doxorubicin 40 or 50mg/m2 IV over 1 hr on day 1 q. 28d, Topotecan 4.0mg/m2 over 30 min on day 1,8 and 15 of a 28 day cycle. For each arm, 1 cycle - 28 days		Trametinib 2 mg po daily continuous treatment, For each arm, 1 cycle = 28 days		Patients randomized to the control arm who crossed over to the experimental arm after disease progression.
All Cause Mortality
	Arm A - Control Arm		Arm B - Experimental Arm		Crossover From Control to Experimental Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	60/127 (47.2%)		51/127 (40.2%)		3/88 (3.4%)
Serious Adverse Events
	Arm A - Control Arm		Arm B - Experimental Arm		Crossover From Control to Experimental Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	43/127 (33.9%)		45/127 (35.4%)		25/88 (28.4%)
Blood and lymphatic system disorders
Anemia	1/127 (0.8%)		4/127 (3.1%)		1/88 (1.1%)
Cardiac disorders
Cardiac Arrest	0/127 (0%)		0/127 (0%)		1/88 (1.1%)
Eye disorders
Eye Disorders - Other	2/127 (1.6%)		2/127 (1.6%)		0/88 (0%)
Retinal Vascular Disorder	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Gastrointestinal disorders
Colonic Obstruction	4/127 (3.1%)		0/127 (0%)		5/88 (5.7%)
Colonic Stenosis	0/127 (0%)		1/127 (0.8%)		1/88 (1.1%)
Colonic Perforation	1/127 (0.8%)		0/127 (0%)		0/88 (0%)
Diarrhea	2/127 (1.6%)		1/127 (0.8%)		0/88 (0%)
Vomiting	1/127 (0.8%)		3/127 (2.4%)		1/88 (1.1%)
Small Intestinal Obstruction	2/127 (1.6%)		11/127 (8.7%)		3/88 (3.4%)
Abdominal Pain	10/127 (7.9%)		2/127 (1.6%)		2/88 (2.3%)
Mucositis Oral	1/127 (0.8%)		1/127 (0.8%)		0/88 (0%)
Lower Gastrointestinal Hemorrhage	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Gastrointestinal Disorders - Other	1/127 (0.8%)		0/127 (0%)		0/88 (0%)
Nausea	5/127 (3.9%)		1/127 (0.8%)		0/88 (0%)
Ascites	1/127 (0.8%)		0/127 (0%)		0/88 (0%)
Jejunal Obstruction	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Obstruction Gastric	0/127 (0%)		0/127 (0%)		2/88 (2.3%)
Ileus	0/127 (0%)		0/127 (0%)		1/88 (1.1%)
General disorders
Pain	1/127 (0.8%)		0/127 (0%)		1/88 (1.1%)
Flu Like Symptoms	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Non-Cardiac Chest Pain	1/127 (0.8%)		0/127 (0%)		0/88 (0%)
Edema Limbs	1/127 (0.8%)		0/127 (0%)		0/88 (0%)
Death Nos	1/127 (0.8%)		2/127 (1.6%)		0/88 (0%)
Hepatobiliary disorders
Cholecystitis	1/127 (0.8%)		0/127 (0%)		0/88 (0%)
Infections and infestations
Infections And Infestations - Other	1/127 (0.8%)		1/127 (0.8%)		0/88 (0%)
Upper Respiratory Infection	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Soft Tissue Infection	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Sepsis	1/127 (0.8%)		2/127 (1.6%)		1/88 (1.1%)
Lung Infection	1/127 (0.8%)		2/127 (1.6%)		0/88 (0%)
Kidney Infection	2/127 (1.6%)		1/127 (0.8%)		0/88 (0%)
Device Related Infection	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Urinary Tract Infection	4/127 (3.1%)		6/127 (4.7%)		2/88 (2.3%)
Skin Infection	0/127 (0%)		0/127 (0%)		1/88 (1.1%)
Lung Infection	0/127 (0%)		0/127 (0%)		1/88 (1.1%)
Injury, poisoning and procedural complications
Intestinal Stoma Obstruction	1/127 (0.8%)		0/127 (0%)		0/88 (0%)
Investigations
Ejection Fraction Decreased	1/127 (0.8%)		2/127 (1.6%)		0/88 (0%)
Neutrophil Count Decreased	1/127 (0.8%)		0/127 (0%)		0/88 (0%)
Alkaline Phosphatase Increased	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Alanine Aminotransferase Increased	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Metabolism and nutrition disorders
Hyponatremia	2/127 (1.6%)		0/127 (0%)		1/88 (1.1%)
Hypokalemia	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Dehydration	2/127 (1.6%)		0/127 (0%)		0/88 (0%)
Anorexia	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Hypoalbuminemia	0/127 (0%)		0/127 (0%)		1/88 (1.1%)
Psychiatric disorders
Delirium	0/127 (0%)		0/127 (0%)		1/88 (1.1%)
Renal and urinary disorders
Renal And Urinary Disorders - Other	0/127 (0%)		1/127 (0.8%)		1/88 (1.1%)
Urinary Tract Obstruction	0/127 (0%)		1/127 (0.8%)		1/88 (1.1%)
Hematuria	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Acute Kidney Injury	1/127 (0.8%)		0/127 (0%)		1/88 (1.1%)
Urinary Retention	0/127 (0%)		0/127 (0%)		1/88 (1.1%)
Reproductive system and breast disorders
Vaginal Hemorrhage	3/127 (2.4%)		0/127 (0%)		1/88 (1.1%)
Respiratory, thoracic and mediastinal disorders
Respiratory Failure	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Pneumonitis	0/127 (0%)		1/127 (0.8%)		1/88 (1.1%)
Pleural Effusion	1/127 (0.8%)		2/127 (1.6%)		2/88 (2.3%)
Dyspnea	2/127 (1.6%)		2/127 (1.6%)		0/88 (0%)
Chylothorax	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Bronchopulmonary Hemorrhage	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Skin and subcutaneous tissue disorders
Skin And Subcutaneous Tissue Disorders - Other	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Rash Maculo-Papular	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Vascular disorders
Thromboembolic Event	1/127 (0.8%)		4/127 (3.1%)		0/88 (0%)
Hypotension	1/127 (0.8%)		0/127 (0%)		0/88 (0%)
Hypertension	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Other (Not Including Serious) Adverse Events
	Arm A - Control Arm		Arm B - Experimental Arm		Crossover From Control to Experimental Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	124/127 (97.6%)		127/127 (100%)		88/88 (100%)
Blood and lymphatic system disorders
Thrombotic Thrombocytopenic Purpura	1/127 (0.8%)		1/127 (0.8%)		0/88 (0%)
Lymph Node Pain	1/127 (0.8%)		1/127 (0.8%)		1/88 (1.1%)
Anemia	54/127 (42.5%)		66/127 (52%)		51/88 (58%)
Febrile Neutropenia	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Cardiac disorders
Atrial Fibrillation	1/127 (0.8%)		1/127 (0.8%)		1/88 (1.1%)
Ventricular Tachycardia	1/127 (0.8%)		0/127 (0%)		0/88 (0%)
Conduction Disorder	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Sinus Bradycardia	0/127 (0%)		4/127 (3.1%)		1/88 (1.1%)
Palpitations	5/127 (3.9%)		5/127 (3.9%)		0/88 (0%)
Left Ventricular Systolic Dysfunction	1/127 (0.8%)		2/127 (1.6%)		0/88 (0%)
Acute Coronary Syndrome	2/127 (1.6%)		0/127 (0%)		1/88 (1.1%)
Pulmonary Valve Disease	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Tricuspid Valve Disease	0/127 (0%)		2/127 (1.6%)		0/88 (0%)
Atrioventricular Block First Degree	0/127 (0%)		1/127 (0.8%)		1/88 (1.1%)
Cardiac Disorders - Other	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Pericardial Effusion	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Sinus Tachycardia	2/127 (1.6%)		8/127 (6.3%)		7/88 (8%)
Mitral Valve Disease	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Cardiac Arrest	0/127 (0%)		0/127 (0%)		2/88 (2.3%)
Heart Failure	0/127 (0%)		0/127 (0%)		1/88 (1.1%)
Chest pain - Cardiac	0/127 (0%)		0/127 (0%)		1/88 (1.1%)
Ear and labyrinth disorders
Middle Ear Inflammation	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Vertigo	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Tinnitus	4/127 (3.1%)		4/127 (3.1%)		1/88 (1.1%)
Hearing Impaired	2/127 (1.6%)		2/127 (1.6%)		2/88 (2.3%)
Ear Pain	1/127 (0.8%)		3/127 (2.4%)		2/88 (2.3%)
Endocrine disorders
Hypothyroidism	2/127 (1.6%)		0/127 (0%)		2/88 (2.3%)
Hyperparathyroidism	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Hyperthyroidism	1/127 (0.8%)		1/127 (0.8%)		0/88 (0%)
Eye disorders
Eye Disorders - Other	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Watering Eyes	2/127 (1.6%)		3/127 (2.4%)		2/88 (2.3%)
Keratitis	1/127 (0.8%)		1/127 (0.8%)		0/88 (0%)
Eye Pain	3/127 (2.4%)		1/127 (0.8%)		0/88 (0%)
Cataract	1/127 (0.8%)		0/127 (0%)		2/88 (2.3%)
Photophobia	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Conjunctivitis	0/127 (0%)		3/127 (2.4%)		2/88 (2.3%)
Retinal Tear	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Retinopathy	1/127 (0.8%)		0/127 (0%)		1/88 (1.1%)
Corneal Ulcer	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Retinal Vascular Disorder	0/127 (0%)		2/127 (1.6%)		0/88 (0%)
Blurred Vision	12/127 (9.4%)		32/127 (25.2%)		13/88 (14.8%)
Dry Eye	7/127 (5.5%)		13/127 (10.2%)		11/88 (12.5%)
Retinal Detachment	0/127 (0%)		2/127 (1.6%)		2/88 (2.3%)
Floaters	0/127 (0%)		4/127 (3.1%)		4/88 (4.5%)
Eyelid Function Disorder	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Flashing lights	0/127 (0%)		0/127 (0%)		1/88 (1.1%)
Gastrointestinal disorders
Dysphagia	3/127 (2.4%)		6/127 (4.7%)		7/88 (8%)
Dyspepsia	8/127 (6.3%)		13/127 (10.2%)		5/88 (5.7%)
Dry Mouth	5/127 (3.9%)		19/127 (15%)		22/88 (25%)
Colonic Obstruction	6/127 (4.7%)		1/127 (0.8%)		7/88 (8%)
Colonic Stenosis	1/127 (0.8%)		1/127 (0.8%)		2/88 (2.3%)
Colonic Perforation	1/127 (0.8%)		0/127 (0%)		0/88 (0%)
Colitis	1/127 (0.8%)		1/127 (0.8%)		2/88 (2.3%)
Colonic Hemorrhage	0/127 (0%)		1/127 (0.8%)		1/88 (1.1%)
Constipation	49/127 (38.6%)		54/127 (42.5%)		31/88 (35.2%)
Diarrhea	43/127 (33.9%)		92/127 (72.4%)		53/88 (60.2%)
Cheilitis	0/127 (0%)		2/127 (1.6%)		2/88 (2.3%)
Vomiting	44/127 (34.6%)		58/127 (45.7%)		33/88 (37.5%)
Bloating	21/127 (16.5%)		21/127 (16.5%)		18/88 (20.5%)
Small Intestinal Perforation	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Stomach Pain	1/127 (0.8%)		3/127 (2.4%)		0/88 (0%)
Small Intestinal Obstruction	9/127 (7.1%)		15/127 (11.8%)		9/88 (10.2%)
Abdominal Pain	60/127 (47.2%)		56/127 (44.1%)		48/88 (54.5%)
Rectal Hemorrhage	4/127 (3.1%)		3/127 (2.4%)		6/88 (6.8%)
Oral Dysesthesia	0/127 (0%)		2/127 (1.6%)		4/88 (4.5%)
Mucositis Oral	23/127 (18.1%)		46/127 (36.2%)		24/88 (27.3%)
Lower Gastrointestinal Hemorrhage	1/127 (0.8%)		2/127 (1.6%)		0/88 (0%)
Oral Hemorrhage	0/127 (0%)		2/127 (1.6%)		2/88 (2.3%)
Ileus	1/127 (0.8%)		0/127 (0%)		2/88 (2.3%)
Gastrointestinal Pain	1/127 (0.8%)		2/127 (1.6%)		1/88 (1.1%)
Oral Pain	1/127 (0.8%)		5/127 (3.9%)		4/88 (4.5%)
Abdominal Distension	6/127 (4.7%)		6/127 (4.7%)		5/88 (5.7%)
Nausea	65/127 (51.2%)		77/127 (60.6%)		48/88 (54.5%)
Gastroparesis	0/127 (0%)		1/127 (0.8%)		1/88 (1.1%)
Gastroesophageal Reflux Disease	10/127 (7.9%)		11/127 (8.7%)		10/88 (11.4%)
Rectal Pain	0/127 (0%)		2/127 (1.6%)		0/88 (0%)
Gastric Fistula	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Fecal Incontinence	3/127 (2.4%)		1/127 (0.8%)		2/88 (2.3%)
Hemorrhoidal Hemorrhage	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Hemorrhoids	1/127 (0.8%)		4/127 (3.1%)		3/88 (3.4%)
Ascites	7/127 (5.5%)		5/127 (3.9%)		2/88 (2.3%)
Toothache	2/127 (1.6%)		1/127 (0.8%)		1/88 (1.1%)
Jejunal Obstruction	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Anal Fistula	1/127 (0.8%)		0/127 (0%)		0/88 (0%)
Dental Caries	1/127 (0.8%)		3/127 (2.4%)		1/88 (1.1%)
Flatulence	2/127 (1.6%)		4/127 (3.1%)		4/88 (4.5%)
Gastritis	0/127 (0%)		2/127 (1.6%)		0/88 (0%)
Enterocolitis	0/127 (0%)		0/127 (0%)		1/88 (1.1%)
Proctitis	0/127 (0%)		0/127 (0%)		1/88 (1.1%)
Periodontal disease	0/127 (0%)		0/127 (0%)		2/88 (2.3%)
Ileus	0/127 (0%)		0/127 (0%)		1/88 (1.1%)
Lip pain	0/127 (0%)		0/127 (0%)		1/88 (1.1%)
Esophageal Stenosis	0/127 (0%)		0/127 (0%)		1/88 (1.1%)
General disorders
Pain	13/127 (10.2%)		25/127 (19.7%)		13/88 (14.8%)
Neck Edema	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Malaise	0/127 (0%)		4/127 (3.1%)		3/88 (3.4%)
Localized Edema	0/127 (0%)		6/127 (4.7%)		7/88 (8%)
Irritability	1/127 (0.8%)		1/127 (0.8%)		0/88 (0%)
Flu Like Symptoms	4/127 (3.1%)		5/127 (3.9%)		1/88 (1.1%)
Edema Trunk	1/127 (0.8%)		3/127 (2.4%)		1/88 (1.1%)
Non-Cardiac Chest Pain	6/127 (4.7%)		7/127 (5.5%)		3/88 (3.4%)
Edema Limbs	15/127 (11.8%)		61/127 (48%)		36/88 (40.9%)
Edema Face	1/127 (0.8%)		10/127 (7.9%)		5/88 (5.7%)
Fatigue	75/127 (59.1%)		92/127 (72.4%)		59/88 (67%)
Fever	13/127 (10.2%)		22/127 (17.3%)		12/88 (13.6%)
Chills	3/127 (2.4%)		15/127 (11.8%)		10/88 (11.4%)
Facial pain	0/127 (0%)		0/127 (0%)		1/88 (1.1%)
Infusion related reaction	0/127 (0%)		0/127 (0%)		1/88 (1.1%)
Multi-Organ failure	0/127 (0%)		0/127 (0%)		1/88 (1.1%)
Hepatobiliary disorders
Portal Vein Thrombosis	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Cholecystitis	2/127 (1.6%)		0/127 (0%)		0/88 (0%)
Immune system disorders
Allergic Reaction	1/127 (0.8%)		8/127 (6.3%)		0/88 (0%)
Infections and infestations
Infections And Infestations - Other	1/127 (0.8%)		1/127 (0.8%)		0/88 (0%)
Wound Infection	4/127 (3.1%)		1/127 (0.8%)		0/88 (0%)
Upper Respiratory Infection	6/127 (4.7%)		14/127 (11%)		0/88 (0%)
Tooth Infection	1/127 (0.8%)		0/127 (0%)		0/88 (0%)
Vulval Infection	1/127 (0.8%)		0/127 (0%)		0/88 (0%)
Soft Tissue Infection	2/127 (1.6%)		1/127 (0.8%)		2/88 (2.3%)
Skin Infection	6/127 (4.7%)		19/127 (15%)		10/88 (11.4%)
Sinusitis	3/127 (2.4%)		7/127 (5.5%)		1/88 (1.1%)
Sepsis	1/127 (0.8%)		4/127 (3.1%)		3/88 (3.4%)
Rhinitis Infective	0/127 (0%)		1/127 (0.8%)		1/88 (1.1%)
Rash Pustular	1/127 (0.8%)		4/127 (3.1%)		4/88 (4.5%)
Pharyngitis	2/127 (1.6%)		0/127 (0%)		1/88 (1.1%)
Otitis Media	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Papulopustular Rash	0/127 (0%)		12/127 (9.4%)		1/88 (1.1%)
Nail Infection	1/127 (0.8%)		4/127 (3.1%)		0/88 (0%)
Mucosal Infection	1/127 (0.8%)		2/127 (1.6%)		1/88 (1.1%)
Lung Infection	2/127 (1.6%)		3/127 (2.4%)		9/88 (10.2%)
Laryngitis	0/127 (0%)		4/127 (3.1%)		0/88 (0%)
Kidney Infection	2/127 (1.6%)		3/127 (2.4%)		1/88 (1.1%)
Paronychia	0/127 (0%)		11/127 (8.7%)		9/88 (10.2%)
Eye Infection	1/127 (0.8%)		4/127 (3.1%)		1/88 (1.1%)
Device Related Infection	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Small Intestine Infection	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Gum Infection	1/127 (0.8%)		0/127 (0%)		0/88 (0%)
Vaginal Infection	2/127 (1.6%)		8/127 (6.3%)		2/88 (2.3%)
Urinary Tract Infection	18/127 (14.2%)		29/127 (22.8%)		14/88 (15.9%)
Bronchial Infection	1/127 (0.8%)		2/127 (1.6%)		1/88 (1.1%)
Enterocolitis Infectious	1/127 (0.8%)		0/127 (0%)		1/88 (1.1%)
Lip Infection	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Anorectal Infection	0/127 (0%)		2/127 (1.6%)		0/88 (0%)
Bladder infection	0/127 (0%)		0/127 (0%)		1/88 (1.1%)
Injury, poisoning and procedural complications
Vascular Access Complication	1/127 (0.8%)		0/127 (0%)		0/88 (0%)
Urostomy Obstruction	1/127 (0.8%)		1/127 (0.8%)		0/88 (0%)
Seroma	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Postoperative Hemorrhage	1/127 (0.8%)		0/127 (0%)		0/88 (0%)
Intestinal Stoma Site Bleeding	1/127 (0.8%)		1/127 (0.8%)		1/88 (1.1%)
Intestinal Stoma Obstruction	1/127 (0.8%)		0/127 (0%)		0/88 (0%)
Fracture	1/127 (0.8%)		0/127 (0%)		2/88 (2.3%)
Fall	2/127 (1.6%)		3/127 (2.4%)		2/88 (2.3%)
Wound Complication	1/127 (0.8%)		0/127 (0%)		1/88 (1.1%)
Dermatitis Radiation	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Burn	0/127 (0%)		7/127 (5.5%)		0/88 (0%)
Intestinal Stoma Leak	1/127 (0.8%)		0/127 (0%)		0/88 (0%)
Bruising	3/127 (2.4%)		6/127 (4.7%)		0/88 (0%)
Prolapse of intestinal stoma	0/127 (0%)		0/127 (0%)		1/88 (1.1%)
Ankle fracture	0/127 (0%)		0/127 (0%)		1/88 (1.1%)
Investigations
Weight Loss	5/127 (3.9%)		8/127 (6.3%)		9/88 (10.2%)
Weight Gain	2/127 (1.6%)		8/127 (6.3%)		2/88 (2.3%)
Platelet Count Decreased	13/127 (10.2%)		22/127 (17.3%)		8/88 (9.1%)
Lymphocyte Count Increased	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Lymphocyte Count Decreased	6/127 (4.7%)		4/127 (3.1%)		2/88 (2.3%)
Lipase Increased	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Inr Increased	1/127 (0.8%)		1/127 (0.8%)		1/88 (1.1%)
Ggt Increased	1/127 (0.8%)		1/127 (0.8%)		2/88 (2.3%)
Electrocardiogram Qt Corrected Interval Prolonged	0/127 (0%)		2/127 (1.6%)		2/88 (2.3%)
Ejection Fraction Decreased	1/127 (0.8%)		10/127 (7.9%)		7/88 (8%)
Creatinine Increased	10/127 (7.9%)		25/127 (19.7%)		15/88 (17%)
Cholesterol High	0/127 (0%)		2/127 (1.6%)		0/88 (0%)
Neutrophil Count Decreased	19/127 (15%)		21/127 (16.5%)		12/88 (13.6%)
Cardiac Troponin I Increased	0/127 (0%)		2/127 (1.6%)		0/88 (0%)
Cpk Increased	0/127 (0%)		2/127 (1.6%)		0/88 (0%)
Cd4 Lymphocytes Decreased	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Blood Bilirubin Increased	0/127 (0%)		2/127 (1.6%)		0/88 (0%)
White Blood Cell Decreased	21/127 (16.5%)		28/127 (22%)		17/88 (19.3%)
Aspartate Aminotransferase Increased	15/127 (11.8%)		47/127 (37%)		27/88 (30.7%)
Alkaline Phosphatase Increased	11/127 (8.7%)		31/127 (24.4%)		15/88 (17%)
Alanine Aminotransferase Increased	13/127 (10.2%)		27/127 (21.3%)		15/88 (17%)
Activated Partial Thromboplastin Time Prolonged	0/127 (0%)		4/127 (3.1%)		1/88 (1.1%)
Metabolism and nutrition disorders
Obesity	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Hypophosphatemia	4/127 (3.1%)		9/127 (7.1%)		4/88 (4.5%)
Hyponatremia	11/127 (8.7%)		16/127 (12.6%)		9/88 (10.2%)
Hypomagnesemia	29/127 (22.8%)		41/127 (32.3%)		28/88 (31.8%)
Hypokalemia	16/127 (12.6%)		27/127 (21.3%)		11/88 (12.5%)
Hypoglycemia	4/127 (3.1%)		5/127 (3.9%)		2/88 (2.3%)
Hypocalcemia	10/127 (7.9%)		25/127 (19.7%)		15/88 (17%)
Hypoalbuminemia	16/127 (12.6%)		42/127 (33.1%)		24/88 (27.3%)
Hypertriglyceridemia	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Hypernatremia	2/127 (1.6%)		8/127 (6.3%)		3/88 (3.4%)
Hypermagnesemia	3/127 (2.4%)		1/127 (0.8%)		1/88 (1.1%)
Hyperkalemia	5/127 (3.9%)		5/127 (3.9%)		5/88 (5.7%)
Hyperglycemia	25/127 (19.7%)		32/127 (25.2%)		16/88 (18.2%)
Hypercalcemia	4/127 (3.1%)		4/127 (3.1%)		1/88 (1.1%)
Dehydration	10/127 (7.9%)		11/127 (8.7%)		7/88 (8%)
Anorexia	24/127 (18.9%)		33/127 (26%)		35/88 (39.8%)
Musculoskeletal and connective tissue disorders
Pain In Extremity	9/127 (7.1%)		9/127 (7.1%)		6/88 (6.8%)
Neck Pain	3/127 (2.4%)		5/127 (3.9%)		3/88 (3.4%)
Myalgia	15/127 (11.8%)		16/127 (12.6%)		10/88 (11.4%)
Muscle Weakness Trunk	1/127 (0.8%)		1/127 (0.8%)		0/88 (0%)
Muscle Weakness Lower Limb	1/127 (0.8%)		0/127 (0%)		0/88 (0%)
Joint Range Of Motion Decreased	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Joint Effusion	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Generalized Muscle Weakness	2/127 (1.6%)		10/127 (7.9%)		6/88 (6.8%)
Flank Pain	2/127 (1.6%)		3/127 (2.4%)		1/88 (1.1%)
Chest Wall Pain	3/127 (2.4%)		3/127 (2.4%)		3/88 (3.4%)
Bone Pain	4/127 (3.1%)		0/127 (0%)		1/88 (1.1%)
Back Pain	24/127 (18.9%)		24/127 (18.9%)		20/88 (22.7%)
Arthritis	3/127 (2.4%)		6/127 (4.7%)		2/88 (2.3%)
Arthralgia	21/127 (16.5%)		11/127 (8.7%)		15/88 (17%)
Musculoskeletal And Connective Tissue Disorder - O	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Muscle weakness upper limb	0/127 (0%)		0/127 (0%)		1/88 (1.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor Pain	1/127 (0.8%)		0/127 (0%)		1/88 (1.1%)
Nervous system disorders
Tremor	0/127 (0%)		4/127 (3.1%)		1/88 (1.1%)
Stroke	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Presyncope	0/127 (0%)		1/127 (0.8%)		1/88 (1.1%)
Peripheral Sensory Neuropathy	28/127 (22%)		36/127 (28.3%)		17/88 (19.3%)
Peripheral Motor Neuropathy	2/127 (1.6%)		5/127 (3.9%)		0/88 (0%)
Paresthesia	6/127 (4.7%)		3/127 (2.4%)		5/88 (5.7%)
Memory Impairment	6/127 (4.7%)		6/127 (4.7%)		4/88 (4.5%)
Lethargy	1/127 (0.8%)		1/127 (0.8%)		2/88 (2.3%)
Headache	24/127 (18.9%)		28/127 (22%)		20/88 (22.7%)
Dysphasia	3/127 (2.4%)		0/127 (0%)		0/88 (0%)
Dysgeusia	4/127 (3.1%)		11/127 (8.7%)		8/88 (9.1%)
Sinus Pain	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Dysarthria	0/127 (0%)		3/127 (2.4%)		0/88 (0%)
Syncope	0/127 (0%)		2/127 (1.6%)		1/88 (1.1%)
Dizziness	7/127 (5.5%)		22/127 (17.3%)		11/88 (12.5%)
Concentration Impairment	1/127 (0.8%)		1/127 (0.8%)		2/88 (2.3%)
Cognitive Disturbance	1/127 (0.8%)		2/127 (1.6%)		1/88 (1.1%)
Psychiatric disorders
Personality Change	1/127 (0.8%)		1/127 (0.8%)		0/88 (0%)
Restlessness	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Libido Decreased	1/127 (0.8%)		0/127 (0%)		0/88 (0%)
Insomnia	24/127 (18.9%)		16/127 (12.6%)		17/88 (19.3%)
Depression	11/127 (8.7%)		26/127 (20.5%)		10/88 (11.4%)
Confusion	1/127 (0.8%)		3/127 (2.4%)		3/88 (3.4%)
Anxiety	12/127 (9.4%)		15/127 (11.8%)		11/88 (12.5%)
Agitation	1/127 (0.8%)		3/127 (2.4%)		0/88 (0%)
Delirium	0/127 (0%)		0/127 (0%)		2/88 (2.3%)
Renal and urinary disorders
Urine Discoloration	1/127 (0.8%)		1/127 (0.8%)		0/88 (0%)
Urinary Urgency	2/127 (1.6%)		8/127 (6.3%)		4/88 (4.5%)
Urinary Tract Obstruction	2/127 (1.6%)		5/127 (3.9%)		3/88 (3.4%)
Urinary Retention	2/127 (1.6%)		4/127 (3.1%)		5/88 (5.7%)
Urinary Incontinence	5/127 (3.9%)		10/127 (7.9%)		5/88 (5.7%)
Urinary Tract Pain	6/127 (4.7%)		10/127 (7.9%)		2/88 (2.3%)
Urinary Frequency	9/127 (7.1%)		10/127 (7.9%)		9/88 (10.2%)
Proteinuria	2/127 (1.6%)		7/127 (5.5%)		3/88 (3.4%)
Hematuria	3/127 (2.4%)		20/127 (15.7%)		4/88 (4.5%)
Cystitis Noninfective	2/127 (1.6%)		1/127 (0.8%)		1/88 (1.1%)
Chronic Kidney Disease	3/127 (2.4%)		1/127 (0.8%)		2/88 (2.3%)
Bladder Spasm	1/127 (0.8%)		2/127 (1.6%)		0/88 (0%)
Acute Kidney Injury	3/127 (2.4%)		0/127 (0%)		4/88 (4.5%)
Reproductive system and breast disorders
Vaginal Pain	1/127 (0.8%)		2/127 (1.6%)		0/88 (0%)
Vaginal Hemorrhage	8/127 (6.3%)		3/127 (2.4%)		6/88 (6.8%)
Vaginal Fistula	1/127 (0.8%)		0/127 (0%)		1/88 (1.1%)
Vaginal Dryness	4/127 (3.1%)		5/127 (3.9%)		2/88 (2.3%)
Uterine Pain	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Pelvic Pain	5/127 (3.9%)		5/127 (3.9%)		2/88 (2.3%)
Menorrhagia	1/127 (0.8%)		0/127 (0%)		0/88 (0%)
Vaginal Discharge	8/127 (6.3%)		3/127 (2.4%)		6/88 (6.8%)
Vaginal Inflammation	1/127 (0.8%)		0/127 (0%)		0/88 (0%)
Dyspareunia	3/127 (2.4%)		2/127 (1.6%)		2/88 (2.3%)
Breast Pain	2/127 (1.6%)		0/127 (0%)		0/88 (0%)
Genital Edema	0/127 (0%)		0/127 (0%)		1/88 (1.1%)
Respiratory, thoracic and mediastinal disorders
Voice Alteration	0/127 (0%)		1/127 (0.8%)		2/88 (2.3%)
Sore Throat	3/127 (2.4%)		6/127 (4.7%)		8/88 (9.1%)
Sneezing	1/127 (0.8%)		2/127 (1.6%)		0/88 (0%)
Sinus Disorder	0/127 (0%)		1/127 (0.8%)		1/88 (1.1%)
Respiratory Failure	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Pulmonary Hypertension	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Postnasal Drip	0/127 (0%)		2/127 (1.6%)		4/88 (4.5%)
Pneumothorax	1/127 (0.8%)		0/127 (0%)		0/88 (0%)
Pneumonitis	0/127 (0%)		3/127 (2.4%)		3/88 (3.4%)
Pleural Effusion	7/127 (5.5%)		6/127 (4.7%)		6/88 (6.8%)
Pharyngeal Mucositis	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Nasal Congestion	5/127 (3.9%)		7/127 (5.5%)		6/88 (6.8%)
Pleuritic Pain	1/127 (0.8%)		1/127 (0.8%)		1/88 (1.1%)
Productive Cough	2/127 (1.6%)		2/127 (1.6%)		6/88 (6.8%)
Laryngeal Inflammation	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Hoarseness	0/127 (0%)		2/127 (1.6%)		6/88 (6.8%)
Sleep Apnea	2/127 (1.6%)		1/127 (0.8%)		3/88 (3.4%)
Hiccups	1/127 (0.8%)		1/127 (0.8%)		1/88 (1.1%)
Epistaxis	1/127 (0.8%)		15/127 (11.8%)		12/88 (13.6%)
Dyspnea	27/127 (21.3%)		44/127 (34.6%)		26/88 (29.5%)
Cough	21/127 (16.5%)		30/127 (23.6%)		19/88 (21.6%)
Chylothorax	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Bronchospasm	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Bronchopulmonary Hemorrhage	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Allergic Rhinitis	6/127 (4.7%)		7/127 (5.5%)		6/88 (6.8%)
Wheezing	0/127 (0%)		0/127 (0%)		1/88 (1.1%)
Hypoxia	0/127 (0%)		0/127 (0%)		1/88 (1.1%)
Respiratory, Thoracic and Mediastinal Disorders	0/127 (0%)		0/127 (0%)		1/88 (1.1%)
Skin and subcutaneous tissue disorders
Urticaria	0/127 (0%)		6/127 (4.7%)		2/88 (2.3%)
Skin Ulceration	2/127 (1.6%)		8/127 (6.3%)		5/88 (5.7%)
Skin Induration	0/127 (0%)		1/127 (0.8%)		0/88 (0%)
Skin Hyperpigmentation	4/127 (3.1%)		3/127 (2.4%)		4/88 (4.5%)
Scalp Pain	0/127 (0%)		2/127 (1.6%)		0/88 (0%)
Rash Acneiform	13/127 (10.2%)		80/127 (63%)		50/88 (56.8%)
Purpura	1/127 (0.8%)		0/127 (0%)		0/88 (0%)
Pruritus	7/127 (5.5%)		25/127 (19.7%)		18/88 (20.5%)
Photosensitivity	0/127 (0%)		4/127 (3.1%)		0/88 (0%)
Periorbital Edema	0/127 (0%)		6/127 (4.7%)		4/88 (4.5%)
Palmar-Plantar Erythrodysesthesia Syndrome	21/127 (16.5%)		8/127 (6.3%)		10/88 (11.4%)
Pain Of Skin	2/127 (1.6%)		4/127 (3.1%)		3/88 (3.4%)
Rash Maculo-Papular	28/127 (22%)		54/127 (42.5%)		30/88 (34.1%)
Nail Ridging	0/127 (0%)		1/127 (0.8%)		1/88 (1.1%)
Nail Loss	1/127 (0.8%)		2/127 (1.6%)		4/88 (4.5%)
Nail Discoloration	3/127 (2.4%)		4/127 (3.1%)		1/88 (1.1%)
Hypertrichosis	0/127 (0%)		3/127 (2.4%)		0/88 (0%)
Hyperhidrosis	1/127 (0.8%)		1/127 (0.8%)		3/88 (3.4%)
Hirsutism	1/127 (0.8%)		4/127 (3.1%)		3/88 (3.4%)
Erythema Multiforme	1/127 (0.8%)		2/127 (1.6%)		0/88 (0%)
Dry Skin	17/127 (13.4%)		56/127 (44.1%)		40/88 (45.5%)
Bullous Dermatitis	0/127 (0%)		2/127 (1.6%)		0/88 (0%)
Alopecia	16/127 (12.6%)		28/127 (22%)		21/88 (23.9%)
Vascular disorders
Thromboembolic Event	6/127 (4.7%)		11/127 (8.7%)		4/88 (4.5%)
Lymphedema	3/127 (2.4%)		5/127 (3.9%)		1/88 (1.1%)
Hypotension	2/127 (1.6%)		5/127 (3.9%)		3/88 (3.4%)
Hypertension	27/127 (21.3%)		49/127 (38.6%)		30/88 (34.1%)
Hot Flashes	35/127 (27.6%)		14/127 (11%)		13/88 (14.8%)
Flushing	3/127 (2.4%)		3/127 (2.4%)		0/88 (0%)
Superior Vena Cava Syndrome	0/127 (0%)		0/127 (0%)		1/88 (1.1%)

Limitations/Caveats

The pERK expression analysis is still under development, and will not be available for approximately 2 - 3 years.

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.