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A Phase I Dose-Escalation Study of Oral ABT-888 (NSC #737664) Plus Intravenous Irinotecan (CPT-11, NSC#616348) Administered in Patients With Advanced Solid Tumors


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Adult Nasal Type Extranodal NK/T-cell Lymphoma, Angioimmunoblastic T-cell Lymphoma, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Nodal Marginal Zone B-cell Lymphoma, 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 Hodgkin Lymphoma, Recurrent Adult Immunoblastic Large Cell Lymphoma, Recurrent Adult Lymphoblastic Lymphoma, Recurrent Adult Non-Hodgkin Lymphoma, Recurrent Adult T-cell Leukemia/Lymphoma, 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, 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 Hodgkin Lymphoma, Stage III Adult Immunoblastic Large Cell Lymphoma, Stage III Adult Lymphoblastic Lymphoma, Stage III Adult Non-Hodgkin Lymphoma, Stage III Adult T-cell Leukemia/Lymphoma, 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 Mycosis Fungoides/Sezary Syndrome, Stage III Small Lymphocytic Lymphoma, 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 Hodgkin Lymphoma, Stage IV Adult Immunoblastic Large Cell Lymphoma, Stage IV Adult Lymphoblastic Lymphoma, Stage IV Adult Non-Hodgkin Lymphoma, Stage IV Adult T-cell Leukemia/Lymphoma, 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 Mycosis Fungoides/Sezary Syndrome, Stage IV Small Lymphocytic Lymphoma, Unspecified Adult Solid Tumor, Protocol Specific, Waldenström Macroglobulinemia

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Trial Information

A Phase I Dose-Escalation Study of Oral ABT-888 (NSC #737664) Plus Intravenous Irinotecan (CPT-11, NSC#616348) Administered in Patients With Advanced Solid Tumors


PRIMARY OBJECTIVES:

I. To determine the optimal biologic dose (OBD) for poly (ADP-ribose) polymerase (PARP)
inhibition using irinotecan (irinotecan hydrochloride) (once weekly intravenously in 2 of 3
weeks), in combination with ABT-888 (twice daily orally for 2 of 3 weeks).

II. To determine the recommended phase II dose (RP2D) for irinotecan (once weekly
intravenously in 2 of 3 weeks), in combination with ABT-888 (twice daily orally for 2 of 3
weeks), determined by evaluating the feasibility, safety, dose limiting toxicities and the
maximally tolerated dose.

III. To determine the safety profile of irinotecan in combination with ABT-888: the
incidence of adverse events (AEs) and clinically significant changes in laboratory tests,
electrocardiograms (ECGs), and vital signs.

IV. To determine the safety profile of irinotecan in combination with ABT-888 at the
recommended phase II dose: the incidence of adverse events (AEs) and clinically significant
changes in laboratory tests, ECGs, and vital signs.

SECONDARY OBJECTIVES:

I. To determine the pharmacokinetic (PK) profile of ABT-888. II. To determine the PK profile
of irinotecan (CPT-11) both as a single agent and in combination with ABT-888.

III. To determine the tumor response as assessed by the Response Evaluation Criteria in
Solid Tumors (RECIST).

TERTIARY OBJECTIVES:

I. Pharmacodynamic (PD) biomarker response: PARP inhibition in peripheral blood mononuclear
cells (PBMC) by measurement of PAR levels. (Dose escalation portion) II. DNA damaging
effects of irinotecan and the combination of irinotecan with ABT-888: levels of γ-H2AX and
Rad51 formation in tumor tissue. (Dose escalation portion) III. Relevance of CYP2C9 and 2C19
polymorphisms, UGT1A1 polymorphism, and ABCG2 polymorphism to the pharmacokinetics of
irinotecan and/or ABT-888. (Dose escalation portion) IV. To explore whether a positive
γ-H2AX response in tumor tissue at 4-6 hrs is reflected in CTCs between 8-24 hrs but not at
4-6 hrs, as predicted. (Expansion portion) V. To explore whether PARP inhibition increases
γH2AX response of CTCs to plasma drug by 4-6 hrs after CPT-11 administration. (Expansion
portion) VI. To explore whether PARP inhibition increases γ-H2AX response of tumor cells to
tissue drug level, as indicated by CTCs at 8-24 hrs after CPT-11. (Expansion portion) VII.
To explore when the γ-H2AX response peak in CTCs occurs, indicating a response in tumor.
(Expansion portion) VIII. To explore whether there is a tumor switch between gamma-H2AX and
ERCC1-mediated repair in the presence of PARP inhibition, (i.e., repeat initial PBMC and
tumor findings). (Expansion portion) IX. To perform analysis of CTCs at day 15 to help guide
alteration in ABT-888 drug administration schedule (continuous administration). (Expansion
portion) X. To sequence the genome and transcriptome from both normal and tumor tissue from
each study patient in the expansion cohort to evaluate point mutations, structural changes
and copy number events. (Expansion portion) XI. To evaluate the damaging effects of
irinotecan and the combination of irinotecan with ABT-888 by examining levels of Rad51
formation in tumors. (Expansion portion) XII. To evaluate the percentage of BCSC in serial
breast tumor biopsies before and after irinotecan alone and after 1 cycle of treatment with
the combination of irinotecan and ABT-888. (Expansion portion) XIII. To perform molecular
profiling of the tumor cell and BCSC populations before and after irinotecan alone and after
1 cycle of treatment with the combination of irinotecan and ABT-888. (Expansion portion)
XIV. To compare Rad51 foci in ALDH+ stem cell populations to the bulk tumor cells.
(Expansion portion)

OUTLINE: This is a dose-escalation study of ABT-888.

Patients receive irinotecan hydrochloride IV over 90 minutes on days 1 and 8 and oral
ABT-888 twice daily on days 0-14 (days 3-14 of course 1 only). Courses repeat every 21 days
in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for 30 days.


Inclusion Criteria:



- Bilirubin =< 1.5 times upper limit of normal (ULN)

- Patients must have tumors determined to be easily accessible for biopsy (e.g.
pleural-based lesions, peripheral lymph nodes, soft tissue metastases, or large liver
metastases)

- Archival tissue block or paraffin sample from archival tissue block (approximately 10
sections) for use in pharmacodynamic correlative studies must be available

- No known active brain metastases

- Patients with previously treated brain metastases are eligible, provided they
are not accompanied by seizures and a baseline brain magnetic resonance imaging
(MRI) scan demonstrates no current evidence of brain metastases

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2 OR Karnofsky PS
60-100%

- Life expectancy > 12 weeks

- Absolute neutrophil count >= 1,500/mm^3

- Platelet count >= 100,000/mm^3

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 times ULN
(=< 5 times ULN if liver metastases are present)

- Alkaline phosphatase =< 2.0 times ULN (=< 5 times ULN if bone or liver metastases are
present)

- Creatinine =< 1.5 times ULN OR creatinine clearance >= 60 mL/min

- Ability to understand and the willingness to sign a written informed consent document

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception prior to, during, and for 3 months
after completion of study treatment

- Must be able to reliably tolerate and/or receive oral medications

- No history of allergic reactions attributed to the following:

- Camptothecin derivatives (e.g., topotecan hydrochloride, irinotecan
hydrochloride, or exatecan mesylate)

- Any ingredients contained within the liquid irinotecan hydrochloride solution
(e.g., sorbitol)

- Any antiemetics or antidiarrheals appropriate for administration with study
therapy (e.g., loperamide or dexamethasone)

- No prior history of seizures

- No uncontrolled intercurrent illness including, but not limited to:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness or social situations that would limit compliance with study
requirements

- More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C)
and recovered

- More than 3 weeks since prior minimal radiotherapy (i.e., =< 5% of total marrow
volume)

- More than 4 weeks since prior radiotherapy (i.e., > 5% of total marrow volume)

- No prior radiotherapy to >= 50% of total marrow volume

- Histologically or cytologically confirmed metastatic or unresectable malignancy
meeting 1 of the following criteria:

- Standard curative or palliative measures do not exist or are no longer effective

- Irinotecan hydrochloride is considered to be a viable therapy regimen

- Patients enrolled on the expansion portion of the study will consist of two cohorts:
those patients who are triple-negative, BRCA-mutant positive and those patients who
have triple-negative, non-BRCA mutated breast cancer

- Patients with solid hematologic malignancies (Hodgkin or non-Hodgkin lymphoma) are
eligible provided a bone marrow has been performed within 6 weeks of treatment

- Measurable disease per Response Evaluation Criteria In Solid Tumors (RECIST)
guidelines

- Patients must be negative for carrying the UGT1A1*28 allele (also called (TA)7)

- More than 4 weeks since prior experimental (i.e., non-Food and Drug Administration
[FDA] approved) therapy or immunotherapy and recovered

- Males receiving treatment for prostate cancer must be maintained at castrate levels
of testosterone by continuation of luteinizing-releasing hormone agonists

- No cytochrome P450 CYP3A4 isoform-inducing drugs (e.g. phenytoin, phenobarbital,
carbamazepine, rifampin, rifabutin, ketoconazole, St. John's Wort)

- No other investigational agents within 4 weeks of study entry

- No chronic growth factor support (e.g., filgrastim [G-CSF], pegfilgrastim) for
maintenance of white blood cell counts or granulocyte counts

- No other concurrent anticancer therapy (cytotoxic, biologic, radiation, or hormonal
other than for replacement) except medications for supportive care that may
potentially have an anticancer effect (i.e., megestrol acetate, bisphosphonates)
started 1 month prior to study

- Patients with active seizure or a history of seizure are excluded

- Patients with known active brain metastases should be excluded from this clinical
trial; patients with prior treated brain metastases are allowed, providing that they
were not accompanied by seizures and that a baseline brain MRI scan prior to study
entry demonstrates no current evidence of brain metastases; all patients with CNS
metastases must be stable for > 3 months after treatment and off steroid treatment
prior to study enrollment

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Optimal biological dose of study drugs, defined as the maximal decrease in PAR

Outcome Time Frame:

Up to day 9 of course 1

Safety Issue:

Yes

Principal Investigator

Patricia LoRusso

Investigator Role:

Principal Investigator

Investigator Affiliation:

Barbara Ann Karmanos Cancer Institute

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-01057

NCT ID:

NCT00576654

Start Date:

December 2007

Completion Date:

Related Keywords:

  • Adult Nasal Type Extranodal NK/T-cell Lymphoma
  • Angioimmunoblastic T-cell Lymphoma
  • Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
  • Nodal Marginal Zone B-cell Lymphoma
  • 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 Hodgkin Lymphoma
  • Recurrent Adult Immunoblastic Large Cell Lymphoma
  • Recurrent Adult Lymphoblastic Lymphoma
  • Recurrent Adult Non-Hodgkin Lymphoma
  • Recurrent Adult T-cell Leukemia/Lymphoma
  • 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
  • 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 Hodgkin Lymphoma
  • Stage III Adult Immunoblastic Large Cell Lymphoma
  • Stage III Adult Lymphoblastic Lymphoma
  • Stage III Adult Non-Hodgkin Lymphoma
  • Stage III Adult T-cell Leukemia/Lymphoma
  • 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 Mycosis Fungoides/Sezary Syndrome
  • Stage III Small Lymphocytic Lymphoma
  • 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 Hodgkin Lymphoma
  • Stage IV Adult Immunoblastic Large Cell Lymphoma
  • Stage IV Adult Lymphoblastic Lymphoma
  • Stage IV Adult Non-Hodgkin Lymphoma
  • Stage IV Adult T-cell Leukemia/Lymphoma
  • 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 Mycosis Fungoides/Sezary Syndrome
  • Stage IV Small Lymphocytic Lymphoma
  • Unspecified Adult Solid Tumor, Protocol Specific
  • Waldenström Macroglobulinemia
  • Burkitt Lymphoma
  • Hodgkin Disease
  • Immunoblastic Lymphadenopathy
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, T-Cell
  • Leukemia-Lymphoma, Adult T-Cell
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin
  • Lymphomatoid Granulomatosis
  • Waldenstrom Macroglobulinemia
  • Mycoses
  • Mycosis Fungoides
  • Sezary Syndrome
  • Lymphoma, B-Cell
  • Lymphoma, Large-Cell, Immunoblastic
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Lymphoma, T-Cell
  • Lymphoma, T-Cell, Cutaneous
  • Lymphoma, B-Cell, Marginal Zone
  • Lymphoma, Extranodal NK-T-Cell
  • Lymphoma, Mantle-Cell

Name

Location

Barbara Ann Karmanos Cancer InstituteDetroit, Michigan  48201
Dana-Farber Cancer InstituteBoston, Massachusetts  02115
University of Maryland Greenebaum Cancer CenterBaltimore, Maryland  21201