Veliparib, Cyclophosphamide, and Doxorubicin Hydrochloride in Treating Patients With Metastatic or Unresectable Solid Tumors or Non-Hodgkin Lymphoma

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00740805
First received: August 22, 2008
Last updated: August 12, 2014
Last verified: July 2014
  Purpose

This phase I trial studies the side effects and best dose of veliparib, cyclophosphamide, and doxorubicin hydrochloride when given together in treating patients solid tumors or non-Hodgkin lymphoma that has spread to other areas of the body or cannot be removed by surgery. Veliparib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cyclophosphamide and doxorubicin hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving veliparib, cyclophosphamide, and doxorubicin hydrochloride may kill more cancer cells.


Condition Intervention Phase
Adult Nasal Type Extranodal NK/T-cell Lymphoma
Anaplastic Large Cell Lymphoma
Angioimmunoblastic T-cell Lymphoma
BRCA1 Mutation Carrier
BRCA2 Mutation Carrier
Cutaneous B-cell Non-Hodgkin Lymphoma
Estrogen Receptor-negative Breast Cancer
Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
Hepatosplenic T-cell Lymphoma
HER2-negative Breast Cancer
Intraocular Lymphoma
Male Breast Cancer
Nodal Marginal Zone B-cell Lymphoma
Noncutaneous Extranodal Lymphoma
Peripheral T-cell Lymphoma
Post-transplant Lymphoproliferative Disorder
Progesterone Receptor-negative Breast Cancer
Recurrent Adult Acute Lymphoblastic Leukemia
Recurrent Adult Burkitt Lymphoma
Recurrent Adult Diffuse Large Cell Lymphoma
Recurrent Adult Diffuse Mixed Cell Lymphoma
Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
Recurrent Adult Grade III Lymphomatoid Granulomatosis
Recurrent Adult Immunoblastic Large Cell Lymphoma
Recurrent Adult Lymphoblastic Lymphoma
Recurrent Adult T-cell Leukemia/Lymphoma
Recurrent Breast Cancer
Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma
Recurrent Grade 1 Follicular Lymphoma
Recurrent Grade 2 Follicular Lymphoma
Recurrent Grade 3 Follicular Lymphoma
Recurrent Mantle Cell Lymphoma
Recurrent Marginal Zone Lymphoma
Recurrent Mycosis Fungoides/Sezary Syndrome
Recurrent Small Lymphocytic Lymphoma
Refractory Chronic Lymphocytic Leukemia
Refractory Hairy Cell Leukemia
Small Intestine Lymphoma
Splenic Marginal Zone Lymphoma
Stage III Adult Burkitt Lymphoma
Stage III Adult Diffuse Large Cell Lymphoma
Stage III Adult Diffuse Mixed Cell Lymphoma
Stage III Adult Diffuse Small Cleaved Cell Lymphoma
Stage III Adult Immunoblastic Large Cell Lymphoma
Stage III Adult Lymphoblastic Lymphoma
Stage III Adult T-cell Leukemia/Lymphoma
Stage III Chronic Lymphocytic Leukemia
Stage III Cutaneous T-cell Non-Hodgkin Lymphoma
Stage III Grade 1 Follicular Lymphoma
Stage III Grade 2 Follicular Lymphoma
Stage III Grade 3 Follicular Lymphoma
Stage III Mantle Cell Lymphoma
Stage III Marginal Zone Lymphoma
Stage III Small Lymphocytic Lymphoma
Stage IIIA Breast Cancer
Stage IIIA Mycosis Fungoides/Sezary Syndrome
Stage IIIB Breast Cancer
Stage IIIB Mycosis Fungoides/Sezary Syndrome
Stage IIIC Breast Cancer
Stage IV Adult Burkitt Lymphoma
Stage IV Adult Diffuse Large Cell Lymphoma
Stage IV Adult Diffuse Mixed Cell Lymphoma
Stage IV Adult Diffuse Small Cleaved Cell Lymphoma
Stage IV Adult Immunoblastic Large Cell Lymphoma
Stage IV Adult Lymphoblastic Lymphoma
Stage IV Adult T-cell Leukemia/Lymphoma
Stage IV Breast Cancer
Stage IV Chronic Lymphocytic Leukemia
Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma
Stage IV Grade 1 Follicular Lymphoma
Stage IV Grade 2 Follicular Lymphoma
Stage IV Grade 3 Follicular Lymphoma
Stage IV Mantle Cell Lymphoma
Stage IV Marginal Zone Lymphoma
Stage IV Small Lymphocytic Lymphoma
Stage IVA Mycosis Fungoides/Sezary Syndrome
Stage IVB Mycosis Fungoides/Sezary Syndrome
T-cell Large Granular Lymphocyte Leukemia
Testicular Lymphoma
Triple-negative Breast Cancer
Unspecified Adult Solid Tumor, Protocol Specific
Waldenström Macroglobulinemia
Drug: veliparib
Drug: cyclophosphamide
Drug: doxorubicin hydrochloride
Other: laboratory biomarker analysis
Other: pharmacological study
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of ABT-888 in Combination With Cyclophosphamide in Solid Tumors or Non-Hodgkin Lymphoma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • MTD, defined as the dose level that no more than 2/6 or 1/3 patients experience DLT and at least 2/3 or 3/6 patients treated with next higher dose level will have had DLT [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
    Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0


Secondary Outcome Measures:
  • Change in pharmacokinetic parameters [ Time Frame: Day 1, course 1 to day 1, course 2 ] [ Designated as safety issue: No ]
    A two way analysis of variance model will be used to compare the PK parameters.

  • Change in gammaH2AX levels (quantification of the time point of maximal DNA damage) [ Time Frame: Baseline to up to day 14 ] [ Designated as safety issue: No ]

Estimated Enrollment: 90
Study Start Date: August 2008
Estimated Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (veliparib, cyclophosphamide, doxorubicin)

GROUP I: Patients receive veliparib PO every 12 hours on days 1-4 and cyclophosphamide IV over 60 minutes on day 3.

GROUP II: Patients receive veliparib PO every 12 hours on days 1-4, cyclophosphamide IV over 60 minutes on day 3, and doxorubicin hydrochloride IV over 15 minutes on day 3.

GROUP III: Patients receive veliparib PO every 12 hours on days 1-7, cyclophosphamide IV over 60 minutes on day 1, and doxorubicin hydrochloride IV over 15 minutes on day 1.

GROUP IV: Patients receive veliparib PO every 12 hours on days 1-14, cyclophosphamide IV over 60 minutes on day 1, and doxorubicin hydrochloride over 15 minutes on day 1.

In all groups, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Drug: veliparib
Given PO
Other Name: ABT-888
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • ADM
  • ADR
  • Adria
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Detailed Description:

PRIMARY OBJECTIVES:

I. Identify the maximally tolerated dose (MTD) and dose limiting toxicity (DLT) of cyclophosphamide when combined with escalating doses of ABT-888 (veliparib).

II. Identify the maximally tolerated dose (MTD) and dose limiting toxicity (DLT) of cyclophosphamide and doxorubicin (doxorubicin hydrochloride) when combined with escalating doses of ABT-888.

SECONDARY OBJECTIVES:

I. Evaluate any effect of ABT-888 on the systemic clearance of parent cyclophosphamide and the dose normalized area under the curve (AUC) of 4-hydroxy (4-OH) cyclophosphamide when used in combination, using historical single-agent cyclophosphamide and 4-OH data.

II. Evaluate any effect of cyclophosphamide administration on the systemic pharmacokinetics of ABT-888 and its primary metabolite A-925088 (M8), by comparing pharmacokinetic (PK) parameters of ABT-888 on day 1 (before cyclophosphamide) and day 3 (with cyclophosphamide administration); PK samples for analysis will not be collected from patients enrolled after 2/15/2012.

III. Evaluate inhibition of poly (adenosine diphosphate [ADP] ribose) polymerase (PARP) using an immunoassay designed to measure PAR levels in baseline and on-study peripheral blood mononuclear cells (PBMC) samples; PBMC samples for PAR analysis will not be collected from patients enrolled after 2/15/2012.

IV. Evaluate gamma H2A histone family, member X (H2AX) at baseline and on-study circulating tumor cell samples to evaluate the point of maximal deoxyribonucleic acid (DNA) damage from the combination of cyclophosphamide and doxorubicin with ABT-888.

OUTLINE: This is a dose-escalation study of veliparib and cyclophosphamide.

GROUP I: Patients receive veliparib orally (PO) every 12 hours on days 1-4 and cyclophosphamide intravenously (IV) over 60 minutes on day 3.

GROUP II: Patients receive veliparib PO every 12 hours on days 1-4, cyclophosphamide IV over 60 minutes on day 3, and doxorubicin hydrochloride IV over 15 minutes on day 3.

GROUP III: Patients receive veliparib PO every 12 hours on days 1-7, cyclophosphamide IV over 60 minutes on day 1, and doxorubicin hydrochloride IV over 15 minutes on day 1.

GROUP IV: Patients receive veliparib PO every 12 hours on days 1-14, cyclophosphamide IV over 60 minutes on day 1, and doxorubicin hydrochloride over 15 minutes on day 1.

In all groups, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective; patients with either solid tumors or non-Hodgkin's lymphoma are eligible

    • At the recommended Phase II dose level, an additional 6 to 12 patients in each group with the following criteria will be enrolled: documented breast cancer (BRCA)1/BRC2 mutation, triple-negative breast cancer defined as estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and human epidermal growth factor receptor (HER)2-negative, or patients who would benefit from a cyclophosphamide-based regimen
    • On the schedule of ABT-888 given for 7 or 14 days, only patients with metastatic breast cancer will be enrolled
  • Patients must be >= 4 weeks since prior chemotherapy or radiation therapy (>= 6 weeks if the last regimen included carmustine [BCNU] or mitomycin C); patients previously treated with cyclophosphamide should not be necessarily excluded
  • Patients with non-Hodgkin's lymphoma that is amenable to hematopoietic stem cell transplantation with curative intent may participate only if stem cell transplant is refused or is not indicated
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Life expectancy of greater than 2 months
  • Hemoglobin >= 9.0 g/dL
  • Absolute neutrophil count (ANC) >= 1,500/uL
  • Platelets >= 100,000/uL
  • Total bilirubin within normal institutional limits
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal (ULN), =< 5 x ULN if known hepatic metastases
  • Creatinine within normal institutional limits OR creatinine clearance >= 60 ml/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Prothrombin time (PT)/international normalized ratio (INR)/partial thromboplastin time (PTT) =< 1.2 X institutional ULN
  • 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 enrolled in a group where the treatment is adriamycin and cycloblastin (AC): ejection fraction >= 50% by multigated acquisition scan (MUGA) or echocardiogram
  • Patients must sign informed consent

Exclusion Criteria:

  • Concurrent administration of any other investigational agent(s)
  • Prior high-dose therapy requiring hematopoietic stem cell transplantation
  • Prior anti-cancer treatments involving radioactive pharmaceuticals
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to ABT-888 and/or cyclophosphamide
  • Patients receiving any medications or substances that are strong inhibitors or strong inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP 3A4), cytochrome P450, family 2, subfamily B, polypeptide 6 (2B6), cytochrome P450, family 2, subfamily C, polypeptide 9 (2C9) or cytochrome P450, family 2, subfamily C, polypeptide 19 (2C19) are prohibited; at the time of screening, if the patient is currently receiving any of the listed prohibited medication(s), the medication(s) must be discontinued for a period of no less than 7 days prior to administration of the first dose of study medication in order for the patient to meet study eligibility except for the following substance where the washout should be 6 months: amiodarone
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, New York Heart Association (NYHA) grade II or greater congestive heart failure
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with ABT-888; these potential risks may also apply to other agents used in this study
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated; NOTE: HIV seropositive patients not receiving combination antiretroviral therapy who have cluster of differentiation (CD)4 cells >= 350/mm^3, no opportunistic infections and meet all eligibility criteria may participate in this study
  • Any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow and retain ABT-888 capsules
  • Patients with gastrointestinal conditions that might predispose for drug intolerability or poor drug absorption (e.g., inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, malabsorption syndrome, active peptic ulcer disease) are excluded; subjects with ulcerative colitis, inflammatory bowel disease, or a partial or complete small bowel obstruction are also excluded
  • Patients with active central nervous system (CNS) metastases are excluded

    • Patients with CNS metastases that have been treated must be off steroid treatment for > 3 months, be asymptomatic and off steroid treatment prior to study enrollment
    • Patients that have symptoms to suggest CNS metastases should have a brain magnetic resonance imaging (MRI) within 28 days of enrollment to confirm the absence of CNS metastases; contrast computed tomography (CT) is acceptable for patients who are unable to undergo a brain MRI
  • Patients with active seizure or a history of active seizure
  • Any other medical, social, or psychological condition that may significantly affect safety and/or compliance
  • Patients enrolled in a group where treatment is AC: prior doxorubicin exposure of > 300 mg/m^2 or equivalent anthracycline exposure (i.e., epirubicin dose > 540 mg/m^2)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00740805

Locations
United States, New Jersey
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, United States, 08903
Sponsors and Collaborators
Investigators
Principal Investigator: Mark Stein Rutgers Cancer Institute of New Jersey
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00740805     History of Changes
Other Study ID Numbers: NCI-2009-00262, NCI-2009-00262, CDR0000600234, 050803, 7998, U01CA099118, U01CA132194, P30CA072720, UM1CA186716
Study First Received: August 22, 2008
Last Updated: August 12, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Neoplasms
Lymphoma, Follicular
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Lymphoma
Leukemia
Syndrome
Breast Neoplasms
Lymphoma, Mantle-Cell
Lymphoma, B-Cell, Marginal Zone
Lymphoma, Large B-Cell, Diffuse
Lymphoma, T-Cell
Lymphoma, B-Cell
Burkitt Lymphoma
Lymphoma, Large-Cell, Immunoblastic
Mycoses
Mycosis Fungoides
Sezary Syndrome
Lymphoma, T-Cell, Cutaneous
Leukemia, T-Cell
Leukemia-Lymphoma, Adult T-Cell
Waldenstrom Macroglobulinemia
Lymphoma, Large-Cell, Anaplastic
Leukemia, Hairy Cell
Lymphomatoid Granulomatosis
Immunoblastic Lymphadenopathy
Lymphoma, Extranodal NK-T-Cell
Triple Negative Breast Neoplasms

ClinicalTrials.gov processed this record on September 18, 2014