Veliparib, Topotecan Hydrochloride, and Filgrastim or Pegfilgrastim in Treating Patients With Persistent or Recurrent Cervical Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01266447
• Collaborator: NRG Oncology (Other)
• Enrollment: 27
• Locations: 78
• Arm: 1
• Duration (Months): 59
• Patients Per Site: 0.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This phase II clinical trial is studying the how well veliparib, topotecan hydrochloride, and filgrastim or pegfilgrastim work in treating patients with persistent or recurrent cervical cancer. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as topotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by blocking them from dividing. Giving veliparib with chemotherapy may kill more tumor cells. Filgrastim or pegfilgrastim may cause the body to make more blood cells and help it recover from the side effects of chemotherapy.

Condition or Disease	Intervention/Treatment	Phase
Cervical Adenocarcinoma; Cervical Adenosquamous Carcinoma; Cervical Small Cell Carcinoma; Cervical Squamous Cell Carcinoma; Recurrent Cervical Carcinoma; Stage III Cervical Cancer; Stage IVA Cervical Cancer; Stage IVB Cervical Cancer	Biological: Filgrastim; Other: Laboratory Biomarker Analysis; Biological: Pegfilgrastim; Drug: Topotecan Hydrochloride; Drug: Veliparib	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To estimate the antitumor activity (objective response rate by RECIST 1.1) of ABT-888 (veliparib) 10 mg administered orally twice a day on days 1 to 5 with topotecan (topotecan hydrochloride) 0.6 mg/m^2 administered IV once daily on days 1 to 5 of each cycle in patients with persistent or recurrent carcinoma of the cervix.

2. To determine the nature and degree of toxicity of ABT-888 and topotecan in patients with persistent or recurrent carcinoma of the cervix.

SECONDARY OBJECTIVES:

1. To determine the duration of progression-free survival and overall survival.

TERTIARY OBJECTIVES:

1. To determine whether evidence of an interaction exists between study treatments and tumor expression of poly(ADP-ribos)ylation of E2 protein, E6/E7 proteins, and p53R2 in relation to progression-free and overall survival or metastasis. (Translational) II. To explore the association between methylation of FanCF and BRCA in pre-treatment tumor samples and pre- and post-treatment biopsy samples and response, progression-free and overall survival of patients, and/or metastasis. (Translational)

OUTLINE:

Patients receive veliparib orally (PO) twice daily and topotecan hydrochloride intravenously (IV) over 30 minutes once daily on days 1-5. Patients also receive, according to institutional standard, filgrastim subcutaneously (SC) beginning on day 6, 7, or 8 and continuing until hematopoietic recovery or pegfilgrastim SC on day 6, 7, or 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Tumor tissue samples may be collected periodically for translational studies.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Evaluation of ABT-888 (NCI Supplied Agent: ABT-888, NSC #737664), Topotecan (NSC # 609699) and Filgrastim or Pegfilgrastim in the Treatment of Persistent or Recurrent Squamous or Non-squamous Cell Carcinoma of the Cervix
• Study Start Date: Feb 1, 2011
• Actual Primary Completion Date: Jan 1, 2016
• Actual Study Completion Date: Jan 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (veliparib, topotecan hydrochloride, filgrastim) Patients receive veliparib PO twice daily and topotecan hydrochloride IV over 30 minutes once daily on days 1-5. Patients also receive, according to institutional standard, filgrastim SC beginning on day 6, 7, or 8 and continuing until hematopoietic recovery or pegfilgrastim SC on day 6, 7, or 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Biological: Filgrastim; Given SC; Other Names: Filgrastim XM02 G-CSF Neupogen r-metHuG-CSF Recombinant Methionyl Human Granulocyte Colony Stimulating Factor rG-CSF Tbo-filgrastim Tevagrastim ; Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Pegfilgrastim; Given SC; Other Names: Filgrastim SD-01 filgrastim-SD/01 HSP-130 Neulasta Pegfilgrastim Biosimilar HSP-130 SD-01 SD-01 sustained duration G-CSF ; Drug: Topotecan Hydrochloride; Given IV; Other Names: Hycamptamine Hycamtin SKF S-104864-A Topotecan HCl topotecan hydrochloride (oral) ; Drug: Veliparib; Given PO; Other Names: ABT-888 PARP-1 inhibitor ABT-888

Outcome Measures

Primary Outcome Measures

1. Tumor Response [Every other cycle for first 6 months; then every 3 months thereafter until disease progression confirmed; and at any other time if clinically indicted based on symptoms or physical signs suggestive of progressive disease. The average time was 2.3 months]

   Complete and Partial Tumor Response as Assessed by RECIST 1.1. Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1), Complete Response (CR), disappearance of all target and non-target lesions without evidence of new lesion; Partial Response (PR), at least 30% decrease in the sum of the longest dimensions (LD) of all target measurable lesions taking as reference the baseline sum of LD with no unequivocal progression of non-target lesions and no evidence of new lesion. Complete or partial response requires confirmation at greater than or equal to 4 weeks from initial documentation.

2. Number of Patients With Dose-limiting Toxicities (in Safety lead-in) [Up to 21 days]

   A dose-limiting toxicity (DLT) is assessed by NCI CTCAE v4, occurring during cycle 1 of therapy.: A dose-limiting toxicity (DLT) is defined as either hematologic or non-hematologic toxicity assessed by NCI CTCAE v4, occurring during cycle 1 of therapy, which cause any of the following: For hematologic toxicity - dose delay of greater than 2 weeks due to failure to recover counts, Treatment related febrile neutropenia, grade 4 neutropenia lasting >7 days, treatment related grade 4 thrombocytopenia or clinically significant bleeding with grade 3 thrombocytopenia. For non-hematologic toxicity; study treatment related grade 3 or 4 non-hematological toxicity (excluding anorexia, constipation, fatigue, hypersensitivity/allergic reaction to one of the study drugs, nausea & vomiting, and grade 3 dehydration), grade 4 nausea and vomiting for >48 hours despite maximum medical management, electrolyte imbalance of > or equal to grade 3 that can be replaced within 48 hours; any drug related death

3. Adverse Events (Grade 3 or Higher) During Treatment Period [During treatment period and up to 30 days after stopping the study treatment.The average of study treatment time was 2.3 months.]

   Number of participants with a maximum grade of 3 or higher during treatment period. Adverse events are graded and categorized using CTCAE v4.0.

Secondary Outcome Measures

1. Progression-free Survival [From study entry to disease progression, death or date of last contact, whichever occurs first, up to 5 years of follow-up.]

   Progression-free survival is the period of time from study entry to time of disease progression, death or date of last contact, whichever occurs first. Progression is defined as at least a 20% increase in the sum of the longest dimensions (LD) of target lesions taking as reference the smallest sum LD recorded since study entry, or unequivocal progression of existing non-target lesions, or the appearance of one or more new lesions, or global deterioration in health status attributable to the disease requiring a change in therapy without objective evidence of progression, or death due to disease without prior objective documentation of progression.

2. Overall Survival [From study entry to death or last contact, up to 5 years of follow-up.]

   Overall survival is defined as the duration of time from study entry to time of death or the date of last contact.

3. Duration of Objective Response [Every other cycle for first 6 months; then every 3 months until disease progression confirmed; and at any other time if clinically indicated based on symptoms or signs suggestive of progressive disease.The average of study treatment time was 2.3 months.]

   Duration of objective response is defined as the duration from the time measurement criteria is met for partial or complete response by RECIST 1.1, whichever is first recorded, until the first date the recurrent or progressive disease is objectively documented. Per Response Evaluation Criteria in Solid Tumors (RECIST) criteria Complete Response (CR), disappearance of all target and non-target lesions without evidence of new lesion; Partial Response (PR), at least 30% decrease in the sum of the longest dimensions (LD) of all target measurable lesions taking as reference the baseline sum of LD with no unequivocal progression of non-target lesions and no evidence of new lesion. Complete or partial response requires confirmation at greater than or equal to 4 weeks from initial documentation.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients must have persistent or recurrent squamous cell carcinoma, adenosquamous carcinoma, adenocarcinoma or non-squamous cell carcinoma of the cervix with documented disease progression; histological documentation of the original primary tumor is required via the pathology report

• All patients must have measurable disease as defined by RECIST 1.1; measurable disease is defined as at least one 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

• Patient must have at least one "target lesion" to be used to assess response on this protocol as defined by RECIST 1.1; tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy

• Patients must not be eligible for a higher priority Gynecologic Oncology Group (GOG) protocol, if one exists; in general, this would refer to any active GOG Phase III protocol or Rare Tumor protocol for the same patient population

• Patients must have a GOG performance status of 0, 1, or 2

• Recovery from effects of recent surgery, radiotherapy, or chemotherapy

• Patients should be free of active infection requiring antibiotics

• Any hormonal therapy directed at the malignant tumor must be discontinued at least one week prior to registration; continuation of hormone replacement therapy is permitted

• Any other prior therapy directed at the malignant tumor, including chemotherapy, biologic/targeted (non-cytotoxic) therapy and immunologic agents must be discontinued at least three weeks prior to registration; all side effects must have resolved to =< grade 1 or stabilized, prior to enrolling on this study

• Any prior radiation therapy must be completed at least 4 weeks prior to registration

• Patients MUST have had one prior systemic chemotherapeutic regimen for management of advanced, metastatic, or recurrent squamous or non-squamous cell carcinoma of the cervix; chemotherapy administered concurrent with primary radiation is not counted as a systemic chemotherapy regimen (e.g.; weekly cisplatin); adjuvant chemotherapy given following the completion of radiation therapy (or concurrent chemotherapy and radiation therapy) is not counted as a systemic chemotherapy regimen (e.g.; paclitaxel and carboplatin for up to 4 cycles)

• Patients who are registered during the safety lead-in portion of this protocol are required to have prior pelvic radiation

• Patients must have NOT received more than one previous cytotoxic chemotherapy regimen (either with single or combination cytotoxic drug therapy)

• Patients are allowed to receive, but are not required to receive, biologic/targeted (non-cytotoxic) therapy as part of their one prior systemic chemotherapeutic regimen; patients are allowed to receive, but are not required to receive, biologic/targeted (non-cytotoxic) therapy for management of recurrent or persistent disease

• Patients MUST not be eligible for further curative intent surgical or pelvic radiation treatment for management of recurrent or persistent disease as determined by treating physicians

• Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl

• Platelets greater than or equal to 100,000/mcl

• Creatinine less than or equal to 1.5 x institutional upper limit normal (ULN)

• Bilirubin less than or equal to 1.5 x ULN

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 3 x ULN

• Alkaline phosphatase less than or equal to 2.5 x ULN

• Neuropathy (sensory and motor) less than or equal to grade 1

• Patients must have signed an approved informed consent and authorization permitting release of personal health information

• Patients must meet pre-entry requirements

• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

• Patients must have the ability to swallow pills whole

Exclusion Criteria:

• Patients are excluded who have had prior therapy with ABT-888 (veliparib), poly (ADP)-ribose polymerase inhibitors, or topotecan

• Patient with a history of other invasive malignancies, with the exception of non-melanoma skin cancer and other specific malignancies are excluded if there is any evidence of other malignancy being present within the last three years; patients are also excluded if their previous cancer treatment contraindicates this protocol therapy

• Patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis OTHER THAN for the treatment of cervical cancer within the last three 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 three years prior to registration, and the patient remains free of recurrent or metastatic disease

• Patients who have received prior chemotherapy for any abdominal or pelvic tumor OTHER THAN for the treatment of cervical cancer within the last three years are excluded; patients may have received prior adjuvant chemotherapy for cancer, provided that it was completed more than three years prior to registration, and that the patient remains free of recurrent or metastatic disease

• Patients with seizures or history of seizures are ineligible

• Patients with history or evidence upon physical examination of central nervous system (CNS) disease, including primary brain tumor, any CNS metastases, or history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or subarachnoid hemorrhage within six months of the first date of treatment on this study, are ineligible; patients with CNS metastases must be stable for > 3 months after treatment and off steroid treatment prior to study enrollment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UC Irvine Health/Chao Family Comprehensive Cancer Center	Orange	California	United States	92868
2	University of Colorado Cancer Center - Anschutz Cancer Pavilion	Aurora	Colorado	United States	80045
3	Smilow Cancer Hospital Care Center at Saint Francis	Hartford	Connecticut	United States	06105
4	The Hospital of Central Connecticut	New Britain	Connecticut	United States	06050
5	Florida Hospital Orlando	Orlando	Florida	United States	32803
6	Memorial University Medical Center	Savannah	Georgia	United States	31404
7	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho	United States	83706
8	Decatur Memorial Hospital	Decatur	Illinois	United States	62526
9	Sudarshan K Sharma MD Limted-Gynecologic Oncology	Hinsdale	Illinois	United States	60521
10	Memorial Medical Center	Springfield	Illinois	United States	62781
11	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
12	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
13	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
14	Saint Joseph Mercy Hospital	Ann Arbor	Michigan	United States	48106-0995
15	Michigan Cancer Research Consortium CCOP	Ann Arbor	Michigan	United States	48106
16	Oakwood Hospital and Medical Center	Dearborn	Michigan	United States	48124
17	Saint John Hospital and Medical Center	Detroit	Michigan	United States	48236
18	Hurley Medical Center	Flint	Michigan	United States	48502
19	Genesys Regional Medical Center	Grand Blanc	Michigan	United States	48439
20	Allegiance Health	Jackson	Michigan	United States	49201
21	Borgess Medical Center	Kalamazoo	Michigan	United States	49001
22	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
23	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007
24	Sparrow Hospital	Lansing	Michigan	United States	48912
25	Saint Mary Mercy Hospital	Livonia	Michigan	United States	48154
26	Saint Joseph Mercy Oakland	Pontiac	Michigan	United States	48341
27	Saint Joseph Mercy Port Huron	Port Huron	Michigan	United States	48060
28	Saint Mary's of Michigan	Saginaw	Michigan	United States	48601
29	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
30	Cancer Research for the Ozarks NCORP	Springfield	Missouri	United States	65804
31	Mercy Hospital Springfield	Springfield	Missouri	United States	65804
32	CoxHealth South Hospital	Springfield	Missouri	United States	65807
33	Women's Cancer Center of Nevada	Las Vegas	Nevada	United States	89169
34	Cooper Hospital University Medical Center	Camden	New Jersey	United States	08103
35	Southwest Gynecologic Oncology Associates Inc	Albuquerque	New Mexico	United States	87106
36	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87106
37	State University of New York Downstate Medical Center	Brooklyn	New York	United States	11203
38	North Shore University Hospital	Manhasset	New York	United States	11030
39	Long Island Jewish Medical Center	New Hyde Park	New York	United States	11040
40	North Shore-LIJ Health System/Center for Advanced Medicine	New Hyde Park	New York	United States	11040
41	Case Western Reserve University	Cleveland	Ohio	United States	44106
42	Riverside Methodist Hospital	Columbus	Ohio	United States	43214
43	Lake University Ireland Cancer Center	Mentor	Ohio	United States	44060
44	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
45	Oklahoma Cancer Specialists and Research Institute-Tulsa	Tulsa	Oklahoma	United States	74146
46	Abington Memorial Hospital	Abington	Pennsylvania	United States	19001
47	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
48	Women and Infants Hospital	Providence	Rhode Island	United States	02905
49	University Medical Center Brackenridge	Austin	Texas	United States	78701
50	Parkland Memorial Hospital	Dallas	Texas	United States	75235
51	Zale Lipshy University Hospital	Dallas	Texas	United States	75235
52	Clements University Hospital	Dallas	Texas	United States	75390
53	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
54	Scott and White Memorial Hospital	Temple	Texas	United States	76508
55	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298
56	PeaceHealth Medical Group PC	Bellingham	Washington	United States	98226
57	Harrison HealthPartners Hematology and Oncology-Bremerton	Bremerton	Washington	United States	98310
58	Harrison Medical Center	Bremerton	Washington	United States	98310
59	Providence Regional Cancer Partnership	Everett	Washington	United States	98201
60	Skagit Valley Hospital Regional Cancer Care Center	Mount Vernon	Washington	United States	98273
61	Harrison HealthPartners Hematology and Oncology-Poulsbo	Poulsbo	Washington	United States	98370
62	Pacific Gynecology Specialists	Seattle	Washington	United States	98104
63	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109
64	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
65	Group Health Cooperative-Seattle	Seattle	Washington	United States	98112
66	Swedish Medical Center-First Hill	Seattle	Washington	United States	98122-4307
67	Northwest Hospital	Seattle	Washington	United States	98133
68	University of Washington Medical Center	Seattle	Washington	United States	98195
69	Olympic Medical Cancer Care Center	Sequim	Washington	United States	98384
70	Cancer Care Northwest - Spokane South	Spokane	Washington	United States	99202
71	Rockwood Cancer Treatment Center-DHEC-Downtown	Spokane	Washington	United States	99204
72	MultiCare Tacoma General Hospital	Tacoma	Washington	United States	98405
73	Saint Joseph Medical Center	Tacoma	Washington	United States	98405
74	Providence Saint Mary Regional Cancer Center	Walla Walla	Washington	United States	99362
75	Wenatchee Valley Hospital and Clinics	Wenatchee	Washington	United States	98801
76	D N Greenwald Center	Mukwonago	Wisconsin	United States	53149
77	Oconomowoc Memorial Hospital-ProHealth Care Inc	Oconomowoc	Wisconsin	United States	53066
78	Waukesha Memorial Hospital	Waukesha	Wisconsin	United States	53188

Sponsors and Collaborators

• National Cancer Institute (NCI)
• NRG Oncology

Investigators

• Principal Investigator: Charles Kunos, NRG Oncology

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01266447
• Other Study ID Numbers: NCI-2011-02659; NCI-2011-02659; GOG-0127W; CDR0000691281; GOG-0127W; GOG-0127W; U10CA180868; U10CA027469
• First Posted: Dec 24, 2010
• Last Update Posted: Aug 8, 2019
• Last Verified: Aug 1, 2019

• Additional relevant MeSH terms: Carcinoma; Uterine Cervical Neoplasms; Carcinoma, Small Cell; Small Cell Lung Carcinoma; Carcinoma, Adenosquamous; Recurrence; Topotecan; Veliparib; Lenograstim

Study Results

Participant Flow

Recruitment Details	The study was activated on 2/7/2011 and closed to accrual on 1/17/2013.

Arm/Group Title	ABT-888, Topotecan and Filgrastim or Pegfilgrastim
Arm/Group Description	ABT-888 10mg administered orally twice a day on days 1 to 5 of each cycle. Topotecan administered at 0.6 mg/m2 intravenously once daily on days 1 to 5 of each cycle. Each cycle of treatment repeats every 21 days until disease progression or adverse effects prohibit further treatment. All patients will receive filgrastim or pegfilgrastim beginning with cycle 1.
Period Title: Overall Study
STARTED	27
COMPLETED	27
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	ABT-888, Topotecan and Filgrastim or Pegfilgrastim
Arm/Group Description	ABT-888 10mg administered orally twice a day on days 1 to 5 of each cycle. Topotecan administered at 0.6 mg/m2 intravenously once daily on days 1 to 5 of each cycle. Each cycle of treatment repeats every 21 days until disease progression or adverse effects prohibit further treatment. All patients will receive filgrastim or pegfilgrastim beginning with cycle 1.
Overall Participants	27
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	25 92.6%
>=65 years	2 7.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.8 (10.1)
Sex: Female, Male (Count of Participants)
Female	27 100%
Male	0 0%
Region of Enrollment (participants) [Number]
United States	27 100%

Outcome Measures

1. Primary Outcome

Title	Tumor Response
Description	Complete and Partial Tumor Response as Assessed by RECIST 1.1. Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1), Complete Response (CR), disappearance of all target and non-target lesions without evidence of new lesion; Partial Response (PR), at least 30% decrease in the sum of the longest dimensions (LD) of all target measurable lesions taking as reference the baseline sum of LD with no unequivocal progression of non-target lesions and no evidence of new lesion. Complete or partial response requires confirmation at greater than or equal to 4 weeks from initial documentation.
Time Frame	Every other cycle for first 6 months; then every 3 months thereafter until disease progression confirmed; and at any other time if clinically indicted based on symptoms or physical signs suggestive of progressive disease. The average time was 2.3 months

Outcome Measure Data

Analysis Population Description

Eligible and Treated Patients

Arm/Group Title	ABT-888, Topotecan and Filgrastim or Pegfilgrastim
Arm/Group Description	ABT-888 10mg administered orally twice a day on days 1 to 5 of each cycle. Topotecan administered at 0.6 mg/m2 intravenously once daily on days 1 to 5 of each cycle. Each cycle of treatment repeats every 21 days until disease progression or adverse effects prohibit further treatment. All patients will receive filgrastim or pegfilgrastim beginning with cycle 1.
Measure Participants	27
Number (90% Confidence Interval) [percentage of participants]	7.4 27.4%

2. Primary Outcome

Title	Number of Patients With Dose-limiting Toxicities (in Safety lead-in)
Description	A dose-limiting toxicity (DLT) is assessed by NCI CTCAE v4, occurring during cycle 1 of therapy.: A dose-limiting toxicity (DLT) is defined as either hematologic or non-hematologic toxicity assessed by NCI CTCAE v4, occurring during cycle 1 of therapy, which cause any of the following: For hematologic toxicity - dose delay of greater than 2 weeks due to failure to recover counts, Treatment related febrile neutropenia, grade 4 neutropenia lasting >7 days, treatment related grade 4 thrombocytopenia or clinically significant bleeding with grade 3 thrombocytopenia. For non-hematologic toxicity; study treatment related grade 3 or 4 non-hematological toxicity (excluding anorexia, constipation, fatigue, hypersensitivity/allergic reaction to one of the study drugs, nausea & vomiting, and grade 3 dehydration), grade 4 nausea and vomiting for >48 hours despite maximum medical management, electrolyte imbalance of > or equal to grade 3 that can be replaced within 48 hours; any drug related death
Time Frame	Up to 21 days

Outcome Measure Data

Analysis Population Description

The first 6 eligible and treated patients who completed the 1st cycle of study treatment or had a DLT prior to completing the first cycle of study treatment

Arm/Group Title	ABT-888, Topotecan and Filgrastim or Pegfilgrastim
Arm/Group Description	ABT-888 10mg administered orally twice a day on days 1 to 5 of each cycle. Topotecan administered at 0.6 mg/m2 intravenously once daily on days 1 to 5 of each cycle. Each cycle of treatment repeats every 21 days until disease progression or adverse effects prohibit further treatment. All patients will receive filgrastim or pegfilgrastim beginning with cycle 1.
Measure Participants	6
Number [participants]	1 3.7%

3. Primary Outcome

Title	Adverse Events (Grade 3 or Higher) During Treatment Period
Description	Number of participants with a maximum grade of 3 or higher during treatment period. Adverse events are graded and categorized using CTCAE v4.0.
Time Frame	During treatment period and up to 30 days after stopping the study treatment.The average of study treatment time was 2.3 months.

Outcome Measure Data

Analysis Population Description

Eligible and treated patients - No statistical analysis provided for adverse events (grade 3 or higher) during treatment period.

Arm/Group Title	ABT-888, Topotecan and Filgrastim or Pegfilgrastim
Arm/Group Description	ABT-888 10mg administered orally twice a day on days 1 to 5 of each cycle. Topotecan administered at 0.6 mg/m2 intravenously once daily on days 1 to 5 of each cycle. Each cycle of treatment repeats every 21 days until disease progression or adverse effects prohibit further treatment. All patients will receive filgrastim or pegfilgrastim beginning with cycle 1.
Measure Participants	27
Leukopenia	6 22.2%
Thrombocytopenia	12 44.4%
Neutropenia	5 18.5%
Anemia	16 59.3%
Other Investigations	4 14.8%
Cardiac Disorders	1 3.7%
Gastrointestinal Disorders	7 25.9%
General Disorders & administration site conditions	5 18.5%
Infections and Infestations	4 14.8%
Metabolism and nutrition disorders	3 11.1%
Musculoskeletal and connective tissue disorders	5 18.5%
Neoplasms benign, malignant and unspecified	1 3.7%
Nervous system disorders	1 3.7%
Renal and urinary disorders	0 0%
Reproductive system and breast disorders	2 7.4%
Respiratory, thoracic and mediastinal disorders	4 14.8%
Surgical and medical procedures	1 3.7%
Vascular disorders	3 11.1%

4. Secondary Outcome

Title	Progression-free Survival
Description	Progression-free survival is the period of time from study entry to time of disease progression, death or date of last contact, whichever occurs first. Progression is defined as at least a 20% increase in the sum of the longest dimensions (LD) of target lesions taking as reference the smallest sum LD recorded since study entry, or unequivocal progression of existing non-target lesions, or the appearance of one or more new lesions, or global deterioration in health status attributable to the disease requiring a change in therapy without objective evidence of progression, or death due to disease without prior objective documentation of progression.
Time Frame	From study entry to disease progression, death or date of last contact, whichever occurs first, up to 5 years of follow-up.

Outcome Measure Data

Analysis Population Description

Eligible and Treated Patients

Arm/Group Title	ABT-888, Topotecan and Filgrastim or Pegfilgrastim
Arm/Group Description	ABT-888 10mg administered orally twice a day on days 1 to 5 of each cycle. Topotecan administered at 0.6 mg/m2 intravenously once daily on days 1 to 5 of each cycle. Each cycle of treatment repeats every 21 days until disease progression or adverse effects prohibit further treatment. All patients will receive filgrastim or pegfilgrastim beginning with cycle 1.
Measure Participants	27
Median (95% Confidence Interval) [months]	2.0

5. Secondary Outcome

Title	Overall Survival
Description	Overall survival is defined as the duration of time from study entry to time of death or the date of last contact.
Time Frame	From study entry to death or last contact, up to 5 years of follow-up.

Outcome Measure Data

Analysis Population Description

Eligible and Treated Patients

Arm/Group Title	ABT-888, Topotecan and Filgrastim or Pegfilgrastim
Arm/Group Description	ABT-888 10mg administered orally twice a day on days 1 to 5 of each cycle. Topotecan administered at 0.6 mg/m2 intravenously once daily on days 1 to 5 of each cycle. Each cycle of treatment repeats every 21 days until disease progression or adverse effects prohibit further treatment. All patients will receive filgrastim or pegfilgrastim beginning with cycle 1.
Measure Participants	27
Median (95% Confidence Interval) [months]	8.2

6. Secondary Outcome

Title	Duration of Objective Response
Description	Duration of objective response is defined as the duration from the time measurement criteria is met for partial or complete response by RECIST 1.1, whichever is first recorded, until the first date the recurrent or progressive disease is objectively documented. Per Response Evaluation Criteria in Solid Tumors (RECIST) criteria Complete Response (CR), disappearance of all target and non-target lesions without evidence of new lesion; Partial Response (PR), at least 30% decrease in the sum of the longest dimensions (LD) of all target measurable lesions taking as reference the baseline sum of LD with no unequivocal progression of non-target lesions and no evidence of new lesion. Complete or partial response requires confirmation at greater than or equal to 4 weeks from initial documentation.
Time Frame	Every other cycle for first 6 months; then every 3 months until disease progression confirmed; and at any other time if clinically indicated based on symptoms or signs suggestive of progressive disease.The average of study treatment time was 2.3 months.

Outcome Measure Data

Analysis Population Description

Eligible and Treated Patients with objective response

Arm/Group Title	ABT-888, Topotecan and Filgrastim or Pegfilgrastim
Arm/Group Description	ABT-888 10mg administered orally twice a day on days 1 to 5 of each cycle. Topotecan administered at 0.6 mg/m2 intravenously once daily on days 1 to 5 of each cycle. Each cycle of treatment repeats every 21 days until disease progression or adverse effects prohibit further treatment. All patients will receive filgrastim or pegfilgrastim beginning with cycle 1.
Measure Participants	2
Median (Full Range) [Months]	5.3

Adverse Events

Time Frame	During treatment period and up to 30 days after stopping the study treatment. The average of study treatment time was 2.3 months.
Arm/Group Title	ABT-888, Topotecan and Filgrastim or Pegfilgrastim
Arm/Group Description	ABT-888 10mg administered orally twice a day on days 1 to 5 of each cycle. Topotecan administered at 0.6 mg/m2 intravenously once daily on days 1 to 5 of each cycle. Each cycle of treatment repeats every 21 days until disease progression or adverse effects prohibit further treatment. All patients will receive filgrastim or pegfilgrastim beginning with cycle 1.
All Cause Mortality
	ABT-888, Topotecan and Filgrastim or Pegfilgrastim
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	ABT-888, Topotecan and Filgrastim or Pegfilgrastim
	Affected / at Risk (%)	# Events
Total	16/27 (59.3%)
Cardiac disorders
Heart Failure	1/27 (3.7%)	1
Gastrointestinal disorders
Vomiting	1/27 (3.7%)	1
Upper Gastrointestinal Hemorrhage	1/27 (3.7%)	1
Small Intestinal Perforation	1/27 (3.7%)	1
Small Intestinal Obstruction	1/27 (3.7%)	1
Abdominal Pain	2/27 (7.4%)	2
General disorders
Death Nos	2/27 (7.4%)	2
Infections and infestations
Infections And Infestations - Other	1/27 (3.7%)	1
Sepsis	1/27 (3.7%)	1
Urinary Tract Infection	1/27 (3.7%)	1
Investigations
Platelet Count Decreased	2/27 (7.4%)	2
Metabolism and nutrition disorders
Hypokalemia	1/27 (3.7%)	1
Musculoskeletal and connective tissue disorders
Pain In Extremity	1/27 (3.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms Benign, Malignant And Unspecified (Incl	1/27 (3.7%)	1
Reproductive system and breast disorders
Pelvic Pain	1/27 (3.7%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory, Thoracic And Mediastinal Disorders	1/27 (3.7%)	1
Respiratory Failure	1/27 (3.7%)	1
Surgical and medical procedures
Surgical And Medical Procedures - Other	1/27 (3.7%)	1
Vascular disorders
Thromboembolic Event	1/27 (3.7%)	1
Other (Not Including Serious) Adverse Events
	ABT-888, Topotecan and Filgrastim or Pegfilgrastim
	Affected / at Risk (%)	# Events
Total	27/27 (100%)
Blood and lymphatic system disorders
Anemia	27/27 (100%)
Cardiac disorders
Heart Failure	1/27 (3.7%)
Sinus Tachycardia	1/27 (3.7%)
Ear and labyrinth disorders
Ear And Labyrinth Disorders - Other	1/27 (3.7%)
Tinnitus	1/27 (3.7%)
Ear Pain	1/27 (3.7%)
Endocrine disorders
Endocrine Disorders - Other	1/27 (3.7%)
Gastrointestinal disorders
Dysphagia	1/27 (3.7%)
Dyspepsia	1/27 (3.7%)
Dry Mouth	1/27 (3.7%)
Constipation	10/27 (37%)
Diarrhea	7/27 (25.9%)
Vomiting	8/27 (29.6%)
Salivary Duct Inflammation	2/27 (7.4%)
Abdominal Pain	7/27 (25.9%)
Rectal Hemorrhage	2/27 (7.4%)
Mucositis Oral	1/27 (3.7%)
Lower Gastrointestinal Hemorrhage	1/27 (3.7%)
Nausea	15/27 (55.6%)
Hemorrhoidal Hemorrhage	1/27 (3.7%)
Ascites	1/27 (3.7%)
Flatulence	1/27 (3.7%)
General disorders
General Disorders And Administration Site Conditio	1/27 (3.7%)
Pain	7/27 (25.9%)
Malaise	1/27 (3.7%)
Localized Edema	1/27 (3.7%)
Non-Cardiac Chest Pain	2/27 (7.4%)
Edema Limbs	2/27 (7.4%)
Fatigue	22/27 (81.5%)
Fever	3/27 (11.1%)
Chills	1/27 (3.7%)
Infections and infestations
Infections And Infestations - Other	1/27 (3.7%)
Upper Respiratory Infection	1/27 (3.7%)
Skin Infection	1/27 (3.7%)
Sinusitis	1/27 (3.7%)
Sepsis	1/27 (3.7%)
Vaginal Infection	1/27 (3.7%)
Urinary Tract Infection	5/27 (18.5%)
Lip Infection	1/27 (3.7%)
Injury, poisoning and procedural complications
Fracture	1/27 (3.7%)
Fall	1/27 (3.7%)
Bruising	4/27 (14.8%)
Investigations
Weight Loss	1/27 (3.7%)
Weight Gain	2/27 (7.4%)
Platelet Count Decreased	23/27 (85.2%)
Lymphocyte Count Decreased	4/27 (14.8%)
Inr Increased	1/27 (3.7%)
Ggt Increased	1/27 (3.7%)
Creatinine Increased	3/27 (11.1%)
Neutrophil Count Decreased	12/27 (44.4%)
Blood Bilirubin Increased	2/27 (7.4%)
White Blood Cell Decreased	15/27 (55.6%)
Aspartate Aminotransferase Increased	2/27 (7.4%)
Alkaline Phosphatase Increased	8/27 (29.6%)
Alanine Aminotransferase Increased	1/27 (3.7%)
Activated Partial Thromboplastin Time Prolonged	1/27 (3.7%)
Metabolism and nutrition disorders
Hypophosphatemia	1/27 (3.7%)
Hyponatremia	3/27 (11.1%)
Hypomagnesemia	8/27 (29.6%)
Hypokalemia	10/27 (37%)
Hypoglycemia	1/27 (3.7%)
Hypocalcemia	6/27 (22.2%)
Hypoalbuminemia	8/27 (29.6%)
Hypernatremia	1/27 (3.7%)
Hyperkalemia	2/27 (7.4%)
Hyperglycemia	7/27 (25.9%)
Anorexia	9/27 (33.3%)
Musculoskeletal and connective tissue disorders
Pain In Extremity	4/27 (14.8%)
Myalgia	2/27 (7.4%)
Musculoskeletal Deformity	1/27 (3.7%)
Generalized Muscle Weakness	1/27 (3.7%)
Flank Pain	2/27 (7.4%)
Bone Pain	1/27 (3.7%)
Back Pain	6/27 (22.2%)
Arthralgia	3/27 (11.1%)
Musculoskeletal And Connective Tissue Disorder -	1/27 (3.7%)
Nervous system disorders
Peripheral Sensory Neuropathy	8/27 (29.6%)
Peripheral Motor Neuropathy	2/27 (7.4%)
Memory Impairment	2/27 (7.4%)
Lethargy	1/27 (3.7%)
Headache	5/27 (18.5%)
Dysgeusia	3/27 (11.1%)
Dysarthria	1/27 (3.7%)
Dizziness	4/27 (14.8%)
Depressed Level Of Consciousness	1/27 (3.7%)
Ataxia	1/27 (3.7%)
Psychiatric disorders
Insomnia	6/27 (22.2%)
Depression	4/27 (14.8%)
Confusion	1/27 (3.7%)
Anxiety	1/27 (3.7%)
Agitation	1/27 (3.7%)
Renal and urinary disorders
Urinary Tract Obstruction	1/27 (3.7%)
Urinary Incontinence	1/27 (3.7%)
Proteinuria	1/27 (3.7%)
Hematuria	3/27 (11.1%)
Cystitis Noninfective	1/27 (3.7%)
Reproductive system and breast disorders
Vaginal Hemorrhage	2/27 (7.4%)
Pelvic Pain	2/27 (7.4%)
Vaginal Discharge	1/27 (3.7%)
Respiratory, thoracic and mediastinal disorders
Postnasal Drip	2/27 (7.4%)
Pleural Effusion	2/27 (7.4%)
Nasal Congestion	2/27 (7.4%)
Productive Cough	1/27 (3.7%)
Hoarseness	1/27 (3.7%)
Dyspnea	8/27 (29.6%)
Cough	6/27 (22.2%)
Atelectasis	1/27 (3.7%)
Allergic Rhinitis	2/27 (7.4%)
Skin and subcutaneous tissue disorders
Skin And Subcutaneous Tissue Disorders - Other	1/27 (3.7%)
Rash Maculo-Papular	2/27 (7.4%)
Hyperhidrosis	1/27 (3.7%)
Erythema Multiforme	1/27 (3.7%)
Dry Skin	2/27 (7.4%)
Alopecia	11/27 (40.7%)
Vascular disorders
Vascular Disorders - Other	1/27 (3.7%)
Thromboembolic Event	4/27 (14.8%)
Lymphedema	3/27 (11.1%)
Hypotension	3/27 (11.1%)
Hypertension	2/27 (7.4%)
Hot Flashes	3/27 (11.1%)
Flushing	1/27 (3.7%)

Limitations/Caveats

[Not Specified]

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.