Combination Chemotherapy With or Without Veliparib in Treating Patients With Stage IV Head and Neck Cancer

Carboplatin-Paclitaxel Induction Chemotherapy and ABT-888 (Veliparib) - a Phase 1/Randomized Phase 2 Study in Patients With Locoregionally Advanced Squamous Cell Carcinoma of the Head and Neck

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01711541

Enrollment

Registered

2012-10-22

Start date

2012-10-22

Completion date

2023-05-15

Last updated

2023-06-07

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Head and Neck Squamous Cell Carcinoma, Stage IVA Oropharyngeal Carcinoma AJCC v7, Stage IVB Oropharyngeal Carcinoma AJCC v7

Brief summary

This partially randomized phase I/II trial studies the side effects and best dose of veliparib when given together with combination chemotherapy and to see how well they work in treating patients with stage IV head and neck cancer. Drugs used in chemotherapy, such as docetaxel, cisplatin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether combination chemotherapy is more effective when given with or without veliparib in treating head and neck cancer.

Detailed description

PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose (MTD), recommended phase II dose, dose limiting toxicity (DLT), and safety of ABT-888 (veliparib) with carboplatin and paclitaxel induction chemotherapy in locoregionally advanced head and neck (LAHNC) patients. (Phase I) II. Compare magnitude of tumor shrinkage (response) following 2 cycles of induction chemotherapy with and without ABT-888 in LAHNC. (Phase II) SECONDARY OBJECTIVES: I. Compare progression-free (PFS), disease-specific (DSS), and overall survival (OS) in subjects treated with or without ABT-888. (Phase II) OUTLINE: This is a phase I, dose-escalation study of veliparib followed by a phase II study. PHASE I: Patients receive veliparib orally (PO) twice daily (BID) on days 1-7, paclitaxel intravenously (IV) over 60 minutes on days 1, 8, and 15, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. Patients then continue on to concomitant chemoradiotherapy. PHASE II: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive veliparib, paclitaxel, and carboplatin as in Phase I. Treatment repeats every 3 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. Within 10 days from completion of course 2, patients begin concomitant chemoradiotherapy. ARM II: Patients receive placebo PO BID on days 1-7. Patients also receive paclitaxel and carboplatin as in Phase I. Treatment repeats every 3 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. Within 10 days from completion of course 2, patients begin concomitant chemoradiotherapy. CONCOMITANT CHEMORADIOTHERAPY: Patients are assigned to 1 of 2 regimens of concomitant chemoradiotherapy based on the guidelines of the institution where they are being treated. OPTION I (CONCOMITANT CHEMORADIATION WITH CISPLATIN): Patients receive cisplatin IV on days 1 and 22 and undergo radiation therapy 5 days per week for 6 weeks. Treatment repeats every 2 weeks for 5 courses. OPTION II (CONCOMITANT CHEMORADIATION WITH TFHX): Patients receive hydroxyurea PO every 12 hours on days 1-5 for up to 11 doses, fluorouracil IV over 120 hours on days 1-5, paclitaxel IV on day 1, and undergo radiation therapy BID on days 1-5. Treatment repeats every 2 weeks for 5 courses. After completion of study treatment, patients are followed up at 2 weeks, 1, 3, 6, 12, 18, 24, 30, 36, 48, and 60 months. Patients who progress will be followed up every 6 months through year 5.

Interventions

DRUGCarboplatin

Given IV

DRUGCisplatin

Given IV

DRUGFluorouracil

Given IV

DRUGHydroxyurea

Given PO

OTHERLaboratory Biomarker Analysis

Correlative studies

DRUGPaclitaxel

Given IV

OTHERPlacebo Administration

Given PO

RADIATIONRadiation Therapy

Undergo radiation therapy

DRUGVeliparib

Given PO

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* PHASE I: * Patients who are treatment naïve, high risk, stage IVa/IVb (all other sites) and histologically proven squamous cell carcinoma of the head and neck (SCCHN) with no definitive evidence of metastatic disease, excluding patients with oropharynx human papillomavirus (HPV)-positive tumors; in summary, those patients eligible are newly diagnosed and treatment naive: * Stage IVa-b squamous cell carcinoma other than oropharyngeal cancer (OPC), or * Oropharyngeal cancer (OPC) HPV-negative, stage IVa-b * PHASE II: * Patients who are treatment naïve, high risk, stage IVa/IVb (all other sites) histologically proven SCCHN with no definitive evidence of metastatic disease; in summary, those patients eligible are: * Stage IVa-b SCCHN other than OPC, or * OPC, HPV-negative, IVa-b, or * OPC, HPV positive, with greater than 10 pack-year smoking history and N2b-N3 disease * PHASE I AND II: * Patients must have at least one measurable site of disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria; i.e., patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as \>= 20 mm with conventional techniques or as \>= 10 mm with spiral computed tomography (CT) scan magnetic resonance imaging (MRI), or calipers by clinical exam * Eastern Cooperative Oncology Group (ECOG) performance status 0-1 * Patients must be able to swallow the drug * Ability to understand and the willingness to sign a written informed consent document * Leukocytes \>= 3,000/mm\^3 * Absolute neutrophil count \>= 1,500/mm\^3 * Platelets \>= 100,000/mm\^3 * Total bilirubin =\< 1.5 institutional upper limit of normal (ULN) * Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) =\< 2.5 x institutional ULN as calculated by Cockcroft-Gault * Creatinine clearance \>= 60 mL/min/1.73 m\^2 for patients with creatinine levels above ULN as calculated by Cockcroft-Gault * Patients who are receiving any other investigational agents are not eligible * Patients with active seizure or a history of seizure are not eligible * Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to ABT-888 or other agents used in study, including Cremophor, carboplatin, paclitaxel, cisplatin, 5-fluorouracil, hydroxyurea, or any compounds of similar chemical or biologic composition are not eligible * Patients with impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of ABT-888 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) are not eligible to participate in this study * Patients with 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 are not eligible to participate in the study * Pregnant women are not eligible to participate in this study; NOTE: women of child bearing potential must have a negative serum or urine pregnancy test within 7 days prior to treatment * 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 she or her partner is participating in this study, she should inform her treating physician immediately; * Breastfeeding should be discontinued if the mother is treated with ABT-888 * Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are not eligible * Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent are not eligible to participate in this study; topical or inhaled corticosteroids are allowed * Patients with other malignancies within the past 2 years, except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin or surgically treated early stage solid tumors are ineligible to participate in this study

Design outcomes

Primary

Measure	Time frame	Description
Dose Limiting Toxicity (Phase I)	Up to 3 weeks	Dose Limiting Toxicity (DLTs) will be assessed during the first cycle of induction chemotherapy. The following events are considered DLTs: Grade 4 neutropenia (ANC \< 500) lasting more than 14 days, Febrile neutropenia, Grade 4 thrombocytopenia, dose delay of greater than 3 weeks due to failure to recover counts, treatment-related grade 3 or grade 4 non-hematological toxicity (excluding alopecia, fatigue, hypersensitivity reaction, nausea, vomiting, constipation, diarrhea, hypokalemia, hypomagnesemia, hypocalcemia, hypophosphatemia, and grade 3 hypertension), a dose delay of greater than 3 weeks for non-hematological toxicity despite replacement of electrolytes, maximum treatment for diarrhea, nausea, vomiting, and hypertension, any drug-related death. The number of patients reporting a DLT are reported below. The maximum tolerated dose (MTD) will be determined as the highest dose where 1 or fewer out of 6 patients reports a DLT.
Relative Change in Tumor Size as Measured by RECIST (Phase II)	From baseline to 6 weeks	Treatment arms will be compared using the nonparametric Wilcoxon rank-sum test.

Secondary

Measure	Time frame	Description
Disease-free Survival (Phase II)	Up to 5 years	Summarized using the method of Kaplan-Meier, and compared between groups using the log-rank test. Multivariate Cox proportional hazards regression models will be used to further explore group differences adjusting for other prognostic factors, as well as to estimate hazard ratios.
Time to Local or Distant Progression (Phase II)	Up to 5 years	Summarized using the method of Kaplan-Meier, and compared between groups using the log-rank test. Multivariate Cox proportional hazards regression models will be used to further explore group differences adjusting for other prognostic factors, as well as to estimate hazard ratios.
Toxicity (Phase I and Phase II)	upt to 5 years	Adverse Events were collected each cycle during treatment and follow-up according to the CTCAE v4.0 guidelines. The worst graded adverse event was determined for each patient. Below is a table of the number of patients that reported a Grade 3 or Grade 4 or Grade 5 as their worst reported event.
OS (Phase II)	Up to 5 years	Summarized using the method of Kaplan-Meier, and compared between groups using the log-rank test. Multivariate Cox proportional hazards regression models will be used to further explore group differences adjusting for other prognostic factors, as well as to estimate hazard ratios.
DSS (Phase II)	Up to 5 years	Summarized using cumulative incidence, and will be compared between groups using Gray's test. Multivariate Cox proportional hazards regression models will be used to further explore group differences adjusting for other prognostic factors, as well as to estimate hazard ratios.
PFS (Phase II)	Up to 5 years	Summarized using the method of Kaplan-Meier, and compared between groups using the log-rank test. Multivariate Cox proportional hazards regression models will be used to further explore group differences adjusting for other prognostic factors, as well as to estimate hazard ratios.

Countries

United States

Participant flow

Pre-assignment details

The study originally opened at Dose Level 0 with a treatment of Docetaxel, cisplatin and flouricil (TPF) in combination with ABT-888 (veliparib). With a concern for the feasibility of this regimen in other reported studies, this study was suspended and re-opened with a treatment of Carboplatin and Paclitaxel in combination with ABT-888.

Participants by arm

Arm	Count
Dose Level 0 ABT-888 doses will be given at 200 mg bid for 7 days in combination with TPF Induction	4
Dose Level 0B ABT-888 doses will be given at 200 mg bid for 7 days in combination with paclitaxel 100 mg/m2 and carboplatin AUC 6.	4
Dose Level 1 ABT-888 doses will be given at 250 mg bid for 7 days in combination with paclitaxel 100 mg/m2 and carboplatin AUC 6.	3
Dose Level 2 ABT-888 doses will be given at 300 mg bid for 7 days in combination with paclitaxel 100 mg/m2 and carboplatin AUC 6.	6
Dose Level 3 ABT-888 doses will be given at 350 mg bid for 7 days in combination with paclitaxel 100 mg/m2 and carboplatin AUC 6.	7
Total	24

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004
Overall Study	Cancel prior to treatment	0	0	0	1	0
Overall Study	Ineligible	0	1	0	0	0

Baseline characteristics

Characteristic	Dose Level 0	Total	Dose Level 3	Dose Level 2	Dose Level 1	Dose Level 0B
Age, Continuous	72.5 years	63.5 years	61 years	63.5 years	67 years	62.5 years
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants	23 Participants	7 Participants	6 Participants	3 Participants	4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	1 Participants	0 Participants	1 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	1 Participants	2 Participants	0 Participants	0 Participants	0 Participants	1 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	1 Participants	1 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	3 Participants	20 Participants	6 Participants	5 Participants	3 Participants	3 Participants
Region of Enrollment United States	4 participants	24 participants	7 participants	6 participants	3 participants	4 participants
Sex: Female, Male Female	1 Participants	10 Participants	3 Participants	2 Participants	1 Participants	3 Participants
Sex: Female, Male Male	3 Participants	14 Participants	4 Participants	4 Participants	2 Participants	1 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	0 / 3	0 / 3	0 / 3	0 / 5	0 / 7
other Total, other adverse events	3 / 3	3 / 3	3 / 3	5 / 5	7 / 7
serious Total, serious adverse events	3 / 3	0 / 3	1 / 3	0 / 5	5 / 7

Outcome results

Primary

Dose Limiting Toxicity (Phase I)

Dose Limiting Toxicity (DLTs) will be assessed during the first cycle of induction chemotherapy. The following events are considered DLTs: Grade 4 neutropenia (ANC \< 500) lasting more than 14 days, Febrile neutropenia, Grade 4 thrombocytopenia, dose delay of greater than 3 weeks due to failure to recover counts, treatment-related grade 3 or grade 4 non-hematological toxicity (excluding alopecia, fatigue, hypersensitivity reaction, nausea, vomiting, constipation, diarrhea, hypokalemia, hypomagnesemia, hypocalcemia, hypophosphatemia, and grade 3 hypertension), a dose delay of greater than 3 weeks for non-hematological toxicity despite replacement of electrolytes, maximum treatment for diarrhea, nausea, vomiting, and hypertension, any drug-related death. The number of patients reporting a DLT are reported below. The maximum tolerated dose (MTD) will be determined as the highest dose where 1 or fewer out of 6 patients reports a DLT.

Time frame: Up to 3 weeks

Population: Dose Level 0 was not included in this outcome due to a change in treatment regimen. On Dose Level 0B, 1 patient was ineligible based on protocol criteria. On dose level 2, 1 patient cancelled prior to treatment, 1 had a dosing error and 1 pt did not complete cycle 1. On Dose Level 3, 1 patient cancelled prior to treatment.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Dose Level 0	Dose Limiting Toxicity (Phase I)	0 Participants
Dose Level 0B	Dose Limiting Toxicity (Phase I)	0 Participants
Dose Level 1	Dose Limiting Toxicity (Phase I)	0 Participants
Dose Level 2	Dose Limiting Toxicity (Phase I)	0 Participants
Dose Level 3	Dose Limiting Toxicity (Phase I)	1 Participants

Primary

Relative Change in Tumor Size as Measured by RECIST (Phase II)

Treatment arms will be compared using the nonparametric Wilcoxon rank-sum test.

Time frame: From baseline to 6 weeks

Population: The Phase II portion of this study never opened and no analysis was planned.

Secondary

Disease-free Survival (Phase II)

Summarized using the method of Kaplan-Meier, and compared between groups using the log-rank test. Multivariate Cox proportional hazards regression models will be used to further explore group differences adjusting for other prognostic factors, as well as to estimate hazard ratios.

Time frame: Up to 5 years