Dose Dense Paclitaxel With Pembrolizumab (MK-3475) in Platinum Resistant Ovarian Cancer

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02440425
• Collaborator: Merck Sharp & Dohme LLC (Industry)
• Enrollment: 42
• Locations: 3
• Arm: 1
• Anticipated Duration (Months): 94.4
• Patients Per Site: 14
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to find out if the combination of Paclitaxel once per week with Pembrolizumab once every 3 weeks will help participants with this disease. Researchers want to find out the effectiveness of the drug combination to improve the delay of cancer progression or death and compare it to historical data for weekly paclitaxel alone, and assess safety.

Condition or Disease	Intervention/Treatment	Phase
Ovarian Cancer	Drug: Pembrolizumab; Drug: Paclitaxel	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 2 Trial of Dose Dense (Weekly) Paclitaxel With Pembrolizumab (MK-3475) in Platinum Resistant Recurrent Ovarian Cancer
• Actual Study Start Date: Oct 20, 2015
• Actual Primary Completion Date: Apr 1, 2020
• Anticipated Study Completion Date: Sep 1, 2023

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Combination Therapy Combination Therapy: Pembrolizumab (experimental use) and Paclitaxel (standard use). All trial treatments will be administered on an outpatient basis. One cycle equals 21 days. The first cycle is 28 days with Pembrolizumab given on day 8 in order to determine paclitaxel tolerance.

Drug: Pembrolizumab; Pembrolizumab: 200 mg, every (Q) 3 weeks, via intravenous (IV) infusion, until progression or toxicity (or up to 24 months). The first cycle will begin on day 8.; Other Names: MK-3475 KEYTRUDA® ; Drug: Paclitaxel; Paclitaxel: 80 mg/m^2, Q week for 3 weeks, via IV infusion, until progression or toxicity (or complete response if at least 6 cycles, at the discretion of the investigator and participant). Cycle 1 will have an extra lead in week (4 weeks total) with Paclitaxel only on week 1.; Other Names: Taxol Onxal

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival (PFS) at 6 Months [6 months]

   6-month progression-free survival of the combination of weekly paclitaxel with pembrolizumab (MK-3475) for those patients who received treatment and were evaluable (had one response assessment scan by RECIST 1.1) . 6-month PFS: The proportion of patients at 6 months alive without progressive disease. Progressive Disease (PD): Sum of the longest diameters (SLD) increased by at least 20% from the smallest value on study (including baseline, if that is the smallest).

2. Occurrence of Adverse Events [2 years, 6 months]

   Safety of the combination of paclitaxel weekly with pembrolizumab every 3 weeks (Q3W). Serious Adverse Events and Adverse Events will be reported in that Results Data section, according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V4.0.

Secondary Outcome Measures

1. Response Rate (RR) [Up to 36 months]

   Proportion of participants who respond to the regimen by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. RECIST v1.1: Complete Response (CR) - Disappearance of all extranodal target lesions. All pathological lymph nodes must have decreased to <10 mm in short axis. Partial Response (PR) - At least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters. RR=CR + PR.

2. Disease Control Rate (DCR) [Up to 36 months]

   DCR: The percentage of participants complete response, partial response and stable disease to a therapeutic intervention in clinical trials of anticancer agents. Stable Disease (SD) - Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. DCR=CR + PR + (SD x 2 mo.)

3. Duration of Response (DOR) [Up to 36 months]

   Duration of Response in months. DOR= Duration from first observation of partial response to the time of disease progression.

4. Median Overall Survival (OS) [Up to 36 months]

   OS: The time from randomization until death from any cause.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Must have confirmation of the histologic diagnosis of high-grade (grade 2-3) epithelial, non-mucinous, non-borderline, ovarian, fallopian tube, or primary peritoneal carcinoma. May be based on original pathology report or review of original slides.

• Willing and able to provide written informed consent/assent and authorization

• ≥ 18 years of age on day of signing informed consent

• Disease must have been persistent or have recurred within 6 months of prior platinum therapy. Disease may not have progressed during prior platinum therapy (i.e., refractory).

• Have measurable disease or detectable (non-measureable) disease

• Measurable disease: must have at least one "target lesion" to be used to assess response on this protocol.

• Prior Therapy:

• Have had one prior platinum-based chemotherapeutic regimen for management of primary disease containing carboplatin, cisplatin, or another organoplatinum compound. This initial treatment may have included intraperitoneal therapy, consolidation, non-cytotoxic agents (biologic/ targeted) or extended therapy administered after surgical or non-surgical assessment. If patients were treated initially with paclitaxel for their primary disease, this can have been given weekly or every 3 weeks. The most recent therapy and any therapies subsequent to initial therapy, however, cannot have contained weekly paclitaxel. If the immediate prior (most recent therapy) is the initial therapy, it may not have been with weekly paclitaxel.

• Allowed to receive (not required to receive), 2 additional cytotoxic regimens for management of recurrent or persistent disease, with no more than 1 non-platinum regimen. Treatment with weekly paclitaxel for recurrent or persistent disease is NOT allowed.

• Allowed to receive(not required to receive), non-cytotoxic (biologic/targeted) therapy as part of their primary treatment regimen. Allowed to receive (not required to receive), non-cytotoxic (biologic/targeted) therapy as part of their treatment for recurrent or persistent disease and/or as treatment for recurrent or persistent disease. If non-cytotoxic (biologic/targeted) therapy is given alone (i.e., not in combination with cytotoxic chemotherapy) it will NOT count as a prior regimen.

• Have tissue from an archival tissue sample that has been identified and confirmed as available for study, or newly obtained core or excisional biopsy of a tumor lesion

• Have received 1 prior regimen must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2. If have received 2 or 3 prior regimens, must have an ECOG Performance Status of 0 or 1.

• Adequate organ function as defined in the protocol

• Recovery from effects of recent surgery, radiotherapy, or chemotherapy: Should be free of active infection requiring antibiotics (with exception of uncomplicated UTI); Any hormonal therapy directed at the malignant tumor must be discontinued at least 2 weeks prior to registration (continuation of hormone replacement therapy is permitted); Any other prior therapy directed at the malignant tumor, including chemotherapy, biologic/targeted and immunologic agents, must be discontinued at least 2 weeks prior to registration and at least 3 weeks before day 1 on trial.

• Women of Childbearing Potential (WOCBP): Negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

• WOCBP willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication.

Exclusion Criteria:

• Have low-grade or non-epithelial cancers, mucinous cancers, and/or borderline low-malignant potential cancers

• Currently participating in/have participated in a study of an investigational agent or is or has been using an investigational device within 4 weeks of the first dose of treatment

• Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment

• Had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to prior therapies

• Had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 3 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. - Note: If received major surgery, must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.

• History of other invasive malignancies (with exception of non-melanoma skin cancer and or in situ cancers that have undergone potentially curative therapy) are excluded if there is any evidence of other malignancy being present within the last 3 years. Patients are also excluded if their previous cancer treatment contraindicates this protocol therapy.

• Have received prior radiotherapy to any portion of the abdominal cavity or pelvis OTHER THAN for the treatment of ovarian, fallopian tube, or primary peritoneal cancer within the last 3 years are excluded. Prior radiation for localized cancer of the breast, head and neck, or skin is permitted, provided that it was completed more than 3 years prior to registration, and the patient remains free of recurrent or metastatic disease.

• Have received prior chemotherapy for any abdominal or pelvic tumor OTHER THAN for the treatment of ovarian, fallopian tube, or primary peritoneal cancer within the last 3 year. May have received prior adjuvant chemotherapy for localized breast cancer, provided that it was completed more than 3 years prior to registration, and the patient remains free of recurrent or metastatic disease.

• History of synchronous endometrial cancer unless all of the following conditions are met: Stage not greater than I-A (FIGO 2010 staging criteria); no more than superficial myometrial invasion (<50%), without vascular or lymphatic invasion; no poorly differentiated subtypes, including papillary serous, clear cell or other FIGO Grade 3 lesions and it has been greater than 3 years since diagnosis and there have been no recurrences.

• Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment.

• Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment..

• Evidence of interstitial lung disease, any active, non-infectious pneumonitis, or known active tuberculosis

• An active infection requiring systemic therapy

• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with participation for the full duration of the trial, or is not in the best interest of the participant, in the opinion of the treating physician or the principal or study investigator.

• Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial

• Pregnant or breastfeeding, or expecting to conceive children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.

• Received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody

• Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)

• Known active Hepatitis B or Hepatitis C

• Received a live vaccine within 30 days prior to the first dose of trial treatment

• Peripheral neuropathy Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or higher

• Known hypersensitivity to pembrolizumab or any of its excipients

• Known hypersensitivity to paclitaxel

• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
2	Duke University	Durham	North Carolina	United States	27710
3	VCU Massey Cancer Center	Richmond	Virginia	United States	23298

Sponsors and Collaborators

• H. Lee Moffitt Cancer Center and Research Institute
• Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Robert Wenham, M.D., H. Lee Moffitt Cancer Center and Research Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 21, 2017

More Information

Additional Information:

• Moffitt Cancer Center Clinical Trials website

Publications

None provided.

• Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• ClinicalTrials.gov Identifier: NCT02440425
• Other Study ID Numbers: MCC-18207
• First Posted: May 12, 2015
• Last Update Posted: Apr 28, 2022
• Last Verified: Apr 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by H. Lee Moffitt Cancer Center and Research Institute: platinum resistant; recurrent; persistent; epithelial; ovarian; fallopian tube; primary peritoneal; carcinoma
• Additional relevant MeSH terms: Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Paclitaxel; Pembrolizumab

Study Results

Participant Flow

Arm/Group Title	Combination Therapy
Arm/Group Description	Combination Therapy: Pembrolizumab (experimental use) and Paclitaxel (standard use). All trial treatments will be administered on an outpatient basis. One cycle equals 21 days. The first cycle is 28 days with Pembrolizumab given on day 8 in order to determine paclitaxel tolerance. Pembrolizumab: Pembrolizumab: 200 mg, every (Q) 3 weeks, via intravenous (IV) infusion, until progression or toxicity (or up to 24 months). The first cycle will begin on day 8. Paclitaxel: Paclitaxel: 80 mg/m^2, Q week for 3 weeks, via IV infusion, until progression or toxicity (or complete response if at least 6 cycles, at the discretion of the investigator and participant). Cycle 1 will have an extra lead in week (4 weeks total) with Paclitaxel only on week 1.
Period Title: Overall Study
STARTED	42
COMPLETED	37
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	Combination Therapy
Arm/Group Description	Combination Therapy: Pembrolizumab (experimental use) and Paclitaxel (standard use). All trial treatments will be administered on an outpatient basis. One cycle equals 21 days. The first cycle is 28 days with Pembrolizumab given on day 8 in order to determine paclitaxel tolerance. Pembrolizumab: Pembrolizumab: 200 mg, every (Q) 3 weeks, via intravenous (IV) infusion, until progression or toxicity (or up to 24 months). The first cycle will begin on day 8. Paclitaxel: Paclitaxel: 80 mg/m^2, Q week for 3 weeks, via IV infusion, until progression or toxicity (or complete response if at least 6 cycles, at the discretion of the investigator and participant). Cycle 1 will have an extra lead in week (4 weeks total) with Paclitaxel only on week 1.
Overall Participants	42
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	25 59.5%
>=65 years	17 40.5%
Sex: Female, Male (Count of Participants)
Female	42 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 7.1%
Not Hispanic or Latino	39 92.9%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 2.4%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	4 9.5%
White	35 83.3%
More than one race	0 0%
Unknown or Not Reported	2 4.8%
Region of Enrollment (participants) [Number]
United States	42 100%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS) at 6 Months
Description	6-month progression-free survival of the combination of weekly paclitaxel with pembrolizumab (MK-3475) for those patients who received treatment and were evaluable (had one response assessment scan by RECIST 1.1) . 6-month PFS: The proportion of patients at 6 months alive without progressive disease. Progressive Disease (PD): Sum of the longest diameters (SLD) increased by at least 20% from the smallest value on study (including baseline, if that is the smallest).
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Evaluable participants

Arm/Group Title	Combination Therapy
Arm/Group Description	Combination Therapy: Pembrolizumab (experimental use) and Paclitaxel (standard use). All trial treatments will be administered on an outpatient basis. One cycle equals 21 days. The first cycle is 28 days with Pembrolizumab given on day 8 in order to determine paclitaxel tolerance. Pembrolizumab: Pembrolizumab: 200 mg, every (Q) 3 weeks, via intravenous (IV) infusion, until progression or toxicity (or up to 24 months). The first cycle will begin on day 8. Paclitaxel: Paclitaxel: 80 mg/m^2, Q week for 3 weeks, via IV infusion, until progression or toxicity (or complete response if at least 6 cycles, at the discretion of the investigator and participant). Cycle 1 will have an extra lead in week (4 weeks total) with Paclitaxel only on week 1.
Measure Participants	37
Median (95% Confidence Interval) [percentage of participants]	58.6 139.5%

2. Primary Outcome

Title	Occurrence of Adverse Events
Description	Safety of the combination of paclitaxel weekly with pembrolizumab every 3 weeks (Q3W). Serious Adverse Events and Adverse Events will be reported in that Results Data section, according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V4.0.
Time Frame	2 years, 6 months

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drugs.

Arm/Group Title	Combination Therapy
Arm/Group Description	Combination Therapy: Pembrolizumab (experimental use) and Paclitaxel (standard use). All trial treatments will be administered on an outpatient basis. One cycle equals 21 days. The first cycle is 28 days with Pembrolizumab given on day 8 in order to determine paclitaxel tolerance. Pembrolizumab: Pembrolizumab: 200 mg, every (Q) 3 weeks, via intravenous (IV) infusion, until progression or toxicity (or up to 24 months). The first cycle will begin on day 8. Paclitaxel: Paclitaxel: 80 mg/m^2, Q week for 3 weeks, via IV infusion, until progression or toxicity (or complete response if at least 6 cycles, at the discretion of the investigator and participant). Cycle 1 will have an extra lead in week (4 weeks total) with Paclitaxel only on week 1.
Measure Participants	42
SAEs related to study treatment	28
AEs related to study treatment	573

3. Secondary Outcome

Title	Response Rate (RR)
Description	Proportion of participants who respond to the regimen by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. RECIST v1.1: Complete Response (CR) - Disappearance of all extranodal target lesions. All pathological lymph nodes must have decreased to <10 mm in short axis. Partial Response (PR) - At least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters. RR=CR + PR.
Time Frame	Up to 36 months

Outcome Measure Data

Analysis Population Description

Evaluable participants

Arm/Group Title	Combination Therapy
Arm/Group Description	Combination Therapy: Pembrolizumab (experimental use) and Paclitaxel (standard use). All trial treatments will be administered on an outpatient basis. One cycle equals 21 days. The first cycle is 28 days with Pembrolizumab given on day 8 in order to determine paclitaxel tolerance. Pembrolizumab: Pembrolizumab: 200 mg, every (Q) 3 weeks, via intravenous (IV) infusion, until progression or toxicity (or up to 24 months). The first cycle will begin on day 8. Paclitaxel: Paclitaxel: 80 mg/m^2, Q week for 3 weeks, via IV infusion, until progression or toxicity (or complete response if at least 6 cycles, at the discretion of the investigator and participant). Cycle 1 will have an extra lead in week (4 weeks total) with Paclitaxel only on week 1.
Measure Participants	37
Median (95% Confidence Interval) [percentage of participants]	51.4 122.4%

4. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	DCR: The percentage of participants complete response, partial response and stable disease to a therapeutic intervention in clinical trials of anticancer agents. Stable Disease (SD) - Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. DCR=CR + PR + (SD x 2 mo.)
Time Frame	Up to 36 months

Outcome Measure Data

Analysis Population Description

Evaluable participants

Arm/Group Title	Combination Therapy
Arm/Group Description	Combination Therapy: Pembrolizumab (experimental use) and Paclitaxel (standard use). All trial treatments will be administered on an outpatient basis. One cycle equals 21 days. The first cycle is 28 days with Pembrolizumab given on day 8 in order to determine paclitaxel tolerance. Pembrolizumab: Pembrolizumab: 200 mg, every (Q) 3 weeks, via intravenous (IV) infusion, until progression or toxicity (or up to 24 months). The first cycle will begin on day 8. Paclitaxel: Paclitaxel: 80 mg/m^2, Q week for 3 weeks, via IV infusion, until progression or toxicity (or complete response if at least 6 cycles, at the discretion of the investigator and participant). Cycle 1 will have an extra lead in week (4 weeks total) with Paclitaxel only on week 1.
Measure Participants	37
Median (95% Confidence Interval) [percentage of participants]	86.5 206%

5. Secondary Outcome

Title	Duration of Response (DOR)
Description	Duration of Response in months. DOR= Duration from first observation of partial response to the time of disease progression.
Time Frame	Up to 36 months

Outcome Measure Data

Analysis Population Description

Evaluable participants

Arm/Group Title	Combination Therapy
Arm/Group Description	Combination Therapy: Pembrolizumab (experimental use) and Paclitaxel (standard use). All trial treatments will be administered on an outpatient basis. One cycle equals 21 days. The first cycle is 28 days with Pembrolizumab given on day 8 in order to determine paclitaxel tolerance. Pembrolizumab: Pembrolizumab: 200 mg, every (Q) 3 weeks, via intravenous (IV) infusion, until progression or toxicity (or up to 24 months). The first cycle will begin on day 8. Paclitaxel: Paclitaxel: 80 mg/m^2, Q week for 3 weeks, via IV infusion, until progression or toxicity (or complete response if at least 6 cycles, at the discretion of the investigator and participant). Cycle 1 will have an extra lead in week (4 weeks total) with Paclitaxel only on week 1.
Measure Participants	37
Median (95% Confidence Interval) [months]	8.8

6. Secondary Outcome

Title	Median Overall Survival (OS)
Description	OS: The time from randomization until death from any cause.
Time Frame	Up to 36 months

Outcome Measure Data

Analysis Population Description

Evaluable participants

Arm/Group Title	Combination Therapy
Arm/Group Description	Combination Therapy: Pembrolizumab (experimental use) and Paclitaxel (standard use). All trial treatments will be administered on an outpatient basis. One cycle equals 21 days. The first cycle is 28 days with Pembrolizumab given on day 8 in order to determine paclitaxel tolerance. Pembrolizumab: Pembrolizumab: 200 mg, every (Q) 3 weeks, via intravenous (IV) infusion, until progression or toxicity (or up to 24 months). The first cycle will begin on day 8. Paclitaxel: Paclitaxel: 80 mg/m^2, Q week for 3 weeks, via IV infusion, until progression or toxicity (or complete response if at least 6 cycles, at the discretion of the investigator and participant). Cycle 1 will have an extra lead in week (4 weeks total) with Paclitaxel only on week 1.
Measure Participants	37
Median (95% Confidence Interval) [months]	26.3

Adverse Events

Time Frame	Adverse events were recorded from Day 1 of treatment through Day 90 after treatment, 4 years, 6 months. All participants who received at least one dose of study drug are included.
Arm/Group Title	Combination Therapy
Arm/Group Description	Combination Therapy: Pembrolizumab (experimental use) and Paclitaxel (standard use). All trial treatments will be administered on an outpatient basis. One cycle equals 21 days. The first cycle is 28 days with Pembrolizumab given on day 8 in order to determine paclitaxel tolerance. Pembrolizumab: Pembrolizumab: 200 mg, every (Q) 3 weeks, via intravenous (IV) infusion, until progression or toxicity (or up to 24 months). The first cycle will begin on day 8. Paclitaxel: Paclitaxel: 80 mg/m^2, Q week for 3 weeks, via IV infusion, until progression or toxicity (or complete response if at least 6 cycles, at the discretion of the investigator and participant). Cycle 1 will have an extra lead in week (4 weeks total) with Paclitaxel only on week 1.
All Cause Mortality
	Combination Therapy
	Affected / at Risk (%)	# Events
Total	25/42 (59.5%)
Serious Adverse Events
	Combination Therapy
	Affected / at Risk (%)	# Events
Total	21/42 (50%)
Blood and lymphatic system disorders
Anemia	1/42 (2.4%)	1
Cardiac disorders
Endocarditis	1/42 (2.4%)	1
Ear and labyrinth disorders
Vertigo	1/42 (2.4%)	1
Endocrine disorders
Adrenal insufficiency	1/42 (2.4%)	1
Gastrointestinal disorders
Gastrointestinal fistula	1/42 (2.4%)	1
Cholecystitis	1/42 (2.4%)	1
Vomiting	2/42 (4.8%)	2
Ascites	2/42 (4.8%)	2
Small intestinal obstruction	2/42 (4.8%)	2
Nausea	1/42 (2.4%)	1
Colonic obstruction	1/42 (2.4%)	1
General disorders
Edema	1/42 (2.4%)	1
Edema limbs	1/42 (2.4%)	1
Edema trunk	1/42 (2.4%)	1
Fatigue	1/42 (2.4%)	1
Cough	2/42 (4.8%)	2
Fever	3/42 (7.1%)	6
Chills	1/42 (2.4%)	1
Infections and infestations
Urinary tract infection	4/42 (9.5%)	4
Sepsis	3/42 (7.1%)	5
Infections and Infestations - Other	1/42 (2.4%)	1
Infections and Infestations-Other	1/42 (2.4%)	1
Investigations
Alanine aminotransferase increased	1/42 (2.4%)	1
Metabolism and nutrition disorders
Dehydration	2/42 (4.8%)	2
Glucose intolerance	1/42 (2.4%)	1
Hyponatremia	1/42 (2.4%)	1
Musculoskeletal and connective tissue disorders
Spinal fracture	1/42 (2.4%)	1
Nervous system disorders
Syncope	1/42 (2.4%)	1
Renal and urinary disorders
Urinary Tract Obstruction	1/42 (2.4%)	2
Acute kidney injury	1/42 (2.4%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/42 (2.4%)	1
Pneumonitis	2/42 (4.8%)	2
Pleural effusion	1/42 (2.4%)	1
Skin and subcutaneous tissue disorders
Pruritus	1/42 (2.4%)	1
Stevens-Johnson syndrome	1/42 (2.4%)	1
Erythroderma	1/42 (2.4%)	1
Vascular disorders
Hypotension	2/42 (4.8%)	2
Other (Not Including Serious) Adverse Events
	Combination Therapy
	Affected / at Risk (%)	# Events
Total	41/42 (97.6%)
Blood and lymphatic system disorders
Anemia	38/42 (90.5%)	205
Leukocytosis	9/42 (21.4%)	23
Cardiac disorders
Sinus tachycardia	4/42 (9.5%)	7
Atrial fibrillation	1/42 (2.4%)	1
Cardiac disorders - Other	1/42 (2.4%)	1
Ear and labyrinth disorders
Hearing impaired	1/42 (2.4%)	1
Vertigo	1/42 (2.4%)	1
Endocrine disorders
Hypothyroidism	4/42 (9.5%)	7
Hyperthyroidism	3/42 (7.1%)	4
Adrenal insufficiency	2/42 (4.8%)	2
Endocrine disorders - Other	1/42 (2.4%)	2
Eye disorders
Eye disorders - Other	3/42 (7.1%)	4
Watering eyes	2/42 (4.8%)	3
Conjunctivitis	1/42 (2.4%)	1
Eye pain	1/42 (2.4%)	1
Gastrointestinal disorders
Nausea	23/42 (54.8%)	38
Diarrhea	19/42 (45.2%)	35
Vomiting	18/42 (42.9%)	27
Bloating	13/42 (31%)	19
Constipation	13/42 (31%)	14
Abdominal pain	11/42 (26.2%)	15
Abdominal distension	5/42 (11.9%)	7
Gastrointestinal disorders - Other	4/42 (9.5%)	5
Mucositis oral	4/42 (9.5%)	5
Ascites	3/42 (7.1%)	4
Gastroesophageal reflux disease	3/42 (7.1%)	3
Dry mouth	2/42 (4.8%)	2
Rectal pain	2/42 (4.8%)	3
Anal hemorrhage	1/42 (2.4%)	1
Colonic obstruction	1/42 (2.4%)	1
Dental caries	1/42 (2.4%)	1
Duodenal obstruction	1/42 (2.4%)	1
Dysphagia	1/42 (2.4%)	2
Gastrointestinal pain	1/42 (2.4%)	1
Hemorrhoids	1/42 (2.4%)	1
Oral hemorrhage	1/42 (2.4%)	1
Small intestinal obstruction	1/42 (2.4%)	1
Stomach pain	1/42 (2.4%)	1
General disorders
Fatigue	31/42 (73.8%)	51
Edema limbs	23/42 (54.8%)	34
Fever	11/42 (26.2%)	17
Pain	11/42 (26.2%)	12
Non-cardiac chest pain	8/42 (19%)	9
Flu-like symptoms	7/42 (16.7%)	7
Chills	6/42 (14.3%)	6
Infusion related reaction	4/42 (9.5%)	4
Edema face	3/42 (7.1%)	3
Malaise	2/42 (4.8%)	2
Edema trunk	1/42 (2.4%)	1
Facial pain	1/42 (2.4%)	1
General disorders and administration site conditions - Other	1/42 (2.4%)	1
Infusion site extravasation	1/42 (2.4%)	1
Localized edema	1/42 (2.4%)	2
Hepatobiliary disorders
Hepatobiliary disorders -Other	1/42 (2.4%)	1
Infections and infestations
Upper respiratory infection	8/42 (19%)	8
Urinary tract infection	8/42 (19%)	10
Nail infection	4/42 (9.5%)	4
Infections and infestations - Other	3/42 (7.1%)	3
Sepsis	2/42 (4.8%)	2
Device related infection	1/42 (2.4%)	1
Papulopustular rash	1/42 (2.4%)	1
Pleural infection	1/42 (2.4%)	1
Salivary gland infection	1/42 (2.4%)	1
Sinusitis	1/42 (2.4%)	1
Tooth infection	1/42 (2.4%)	1
Injury, poisoning and procedural complications
Bruising	1/42 (2.4%)	1
Fall	1/42 (2.4%)	1
Investigations
Investigations - Other	29/42 (69%)	103
Neutrophil count decreased	27/42 (64.3%)	100
White blood cell count decreased	23/42 (54.8%)	121
Lymphocyte count decreased	22/42 (52.4%)	104
Alkaline phosphatase increased	16/42 (38.1%)	34
Aspartate aminotransferase increased	14/42 (33.3%)	18
Activated partial thromboplastin time prolonged	13/42 (31%)	26
Alanine aminotransferase increased	12/42 (28.6%)	14
Platelet count decreased	11/42 (26.2%)	17
Creatinine increased	4/42 (9.5%)	10
INR increased	4/42 (9.5%)	4
CPK increased	2/42 (4.8%)	4
Weight gain	2/42 (4.8%)	3
Blood bilirubin increased	1/42 (2.4%)	1
Cholesterol high	1/42 (2.4%)	1
Urine output decreased	1/42 (2.4%)	1
Weight loss	1/42 (2.4%)	1
Metabolism and nutrition disorders
Hypomagnesemia	18/42 (42.9%)	43
Hypoalbuminemia	15/42 (35.7%)	35
Anorexia	14/42 (33.3%)	16
Hyponatremia	12/42 (28.6%)	18
Hyperkalemia	10/42 (23.8%)	17
Hypocalcemia	10/42 (23.8%)	14
Hypokalemia	10/42 (23.8%)	15
Hyperglycemia	7/42 (16.7%)	11
Hypophosphatemia	7/42 (16.7%)	7
Dehydration	6/42 (14.3%)	6
Hypercalcemia	6/42 (14.3%)	7
Hyperuricemia	5/42 (11.9%)	6
Hypertriglyceridemia	2/42 (4.8%)	2
Glucose intolerance	1/42 (2.4%)	2
Hypermagnesemia	1/42 (2.4%)	1
Musculoskeletal and connective tissue disorders
Back pain	11/42 (26.2%)	14
Myalgia	7/42 (16.7%)	7
Arthralgia	5/42 (11.9%)	5
Pain in extremity	5/42 (11.9%)	10
Flank pain	4/42 (9.5%)	4
Bone pain	3/42 (7.1%)	7
Generalized muscle weakness	3/42 (7.1%)	3
Muscle weakness, lower limb	1/42 (2.4%)	1
Neck pain	1/42 (2.4%)	1
Osteoporosis	1/42 (2.4%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified - Other	3/42 (7.1%)	3
Nervous system disorders
Headache	10/42 (23.8%)	11
Peripheral sensory neuropathy	10/42 (23.8%)	21
Peripheral motor neuropathy	9/42 (21.4%)	12
Dizziness	8/42 (19%)	10
Dysgeusia	3/42 (7.1%)	3
Parasthesia	2/42 (4.8%)	2
Somnolence	2/42 (4.8%)	3
Syncope	2/42 (4.8%)	2
Amnesia	1/42 (2.4%)	1
Concentration impairment	1/42 (2.4%)	1
Neuralgia	1/42 (2.4%)	1
Presyncope	1/42 (2.4%)	1
Tremor	1/42 (2.4%)	1
Psychiatric disorders
Insomnia	8/42 (19%)	9
Anxiety	5/42 (11.9%)	5
Depression	3/42 (7.1%)	3
Confusion	2/42 (4.8%)	2
Restlessness	2/42 (4.8%)	2
Renal and urinary disorders
Hematuria	4/42 (9.5%)	6
Proteniuria	4/42 (9.5%)	8
Renal and urinary disorders -Other	3/42 (7.1%)	4
Urinary incontinence	3/42 (7.1%)	4
Acute kidney injury	2/42 (4.8%)	2
Urinary frequency	2/42 (4.8%)	2
Urinary urgency	2/42 (4.8%)	2
Bladder spasm	1/42 (2.4%)	1
Cystitis noninfective	1/42 (2.4%)	1
Urinary tract obstruction	1/42 (2.4%)	1
Urinary tract pain	1/42 (2.4%)	1
Reproductive system and breast disorders
Pelvic pain	6/42 (14.3%)	6
Vaginal discharge	2/42 (4.8%)	2
Reproductive system and breast disorders - Other	1/42 (2.4%)	1
Vaginal hemorrhage	1/42 (2.4%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	21/42 (50%)	32
Cough	14/42 (33.3%)	21
Epistaxis	7/42 (16.7%)	7
Pleural effusion	6/42 (14.3%)	12
Allergic rhinitis	4/42 (9.5%)	6
Nasal congestion	4/42 (9.5%)	4
Pneumonitis	2/42 (4.8%)	4
Sore throat	2/42 (4.8%)	2
Atelectasis	1/42 (2.4%)	1
Hoarseness	1/42 (2.4%)	1
Productive cough	1/42 (2.4%)	1
Pulmonary hypertension	1/42 (2.4%)	1
Skin and subcutaneous tissue disorders
Rash maculo-papular	15/42 (35.7%)	24
Alopecia	14/42 (33.3%)	14
Skin and subcutaneous tissue disorders - Other	8/42 (19%)	14
Nail loss	7/42 (16.7%)	8
Pruritus	6/42 (14.3%)	8
Nail discoloration	5/42 (11.9%)	5
Rash acneiform	4/42 (9.5%)	6
Dry skin	3/42 (7.1%)	4
Bulbous dermatitis	1/42 (2.4%)	1
Erythema multiforme	1/42 (2.4%)	1
Nail ridging	1/42 (2.4%)	1
Periorbital edema	1/42 (2.4%)	1
Skin hyperpigmentation	1/42 (2.4%)	1
Stevens-Johnson syndrome	1/42 (2.4%)	1
Vascular disorders
Hypertension	9/42 (21.4%)	41
Hypotension	6/42 (14.3%)	8
Flushing	2/42 (4.8%)	2
Hot flashes	2/42 (4.8%)	2
Lymphedema	1/42 (2.4%)	1
Superior vena cava syndrome	1/42 (2.4%)	1

Limitations/Caveats

Primary outcome only incorporated patients who received treatment & completed first RECIST 1.1 response assessment. Does not reflect an intent-to-treat population. All patients enrolled & received one dose of drug were included for safety analysis. Although patients had a recurrence of cancer within 6 months of a platinum drug ("platinum-resistant"), 43% of patients were enrolled on study >6 months from last platinum-based therapy (including maintenance) & 16.2% were greater than 12 months.

More Information

Certain Agreements

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

The study may be presented at scientific meetings by any of the study investigators with the approval of the Sponsor and also allowing time for prior review by Merck. Intent to submit should be made no later than 4 weeks before a submission is due, and a copy of an abstract or presentation should be submitted no later than 3 weeks prior to finalization or submission to allow time to review.