Phase II Randomized Trial of ABT-888 in Combination With Metronomic Oral Cyclophosphamide in Refractory BRCA-Positive Ovarian, Primary Peritoneal, Ovarian High-Grade Serous Carcinoma, Fallopian Tube Cancer, or Triple-Negative Breast Cancer
Background:
- The poly (ADP-ribose) polymerase (PARP) family of enzymes is critical for maintaining
genomic stability by regulating a variety of DNA repair mechanisms.
- Individuals with deleterious mutations in the BRCA1 or BRCA2 tumor suppressor genes have
an increased risk of developing breast and ovarian cancers due to impaired or defective
DNA damage repair; these individuals have an increased susceptibility to DNA-damaging
agents and PARP inhibitors. Inhibition of PARP inhibits the repair of DNA damage caused
by alkylating agents such as cyclophosphamide.
- Metronomic cyclophosphamide has demonstrated efficacy in several tumor types. The PARP
inhibitor ABT-888 has been shown to potentiate the action of cyclophosphamide in
xenograft models. This combination is well tolerated in a Phase I study and showing
promising activity.
Objectives:
- Compare the response rate (complete response (CR) + partial response (PR)) of the
combination of ABT-888 with metronomic oral cyclophosphamide to the response rate
(CR+PR) of metronomic oral cyclophosphamide in patients with deleterious BRCA mutations
and refractory ovarian cancer or patients with primary peritoneal or ovarian high-grade
serous carcinoma or fallopian tube cancer.
- Compare the response rate (CR+PR) of the combination of ABT-888 with metronomic oral
cyclophosphamide to the response rate (CR+PR) of single-agent oral cyclophosphamide in
patients with triple-negative metastatic breast cancer, stratified for deleterious BRCA
mutation.
- Compare the response rate (CR+PR) of the combination of ABT-888 with metronomic oral
cyclophosphamide to the response rate (CR+PR) of single-agent metronomic oral
cyclophosphamide in patients with refractory low-grade lymphomas.
Secondary Objectives:
- Determine PAR levels in tumor biopsies, evaluate in archival tissue whether patients tumors
have mutations in genes involved in DNA damage repair (e.g., BRCA/Fanconi anemia/protein 53
(p53)), perform exploratory gene expression profiling to correlate PARP messenger ribonucleic
acid (mRNA) levels or BRCA mutation status with response to therapy, count circulating tumor
cells (CTCs), and determine H2AX levels in CTCs and tumor biopsies (National Cancer Institute
(NCI) clinical center only).
Eligibility:
-Adults with refractory BRCA-positive ovarian cancer, primary peritoneal or ovarian
high-grade serous carcinoma, fallopian tube cancer, triple-negative breast cancer, or
low-grade lymphoid malignancies (non-Hodgkin's lymphoma) whose disease has progressed
following at least one line of therapy.
Study Design:
- This is a randomized, multi-histology Phase II trial with patients enrolled into 3
cohorts: BRCA-positive ovarian cancer or primary peritoneal or ovarian high-grade serous
carcinoma or fallopian tube cancer (A); triple-negative breast cancer (B); or low grade
non-Hodgkin's lymphoma (C). Patients in cohort A will be randomized to the combination
of ABT-888 with metronomic oral cyclophosphamide or metronomic oral cyclophosphamide
alone. Patients in cohort B will be randomized to the combination of ABT-888 with
metronomic oral cyclophosphamide or metronomic oral cyclophosphamide alone. Patients in
cohort C will be randomized to the combination of ABT-888 with metronomic oral
cyclophosphamide or metronomic oral cyclophosphamide alone.
- Cyclophosphamide (50 mg) and ABT-888 (60 mg) will be administered orally once a day,
continuously in 21-day cycles.
Phase I Open Label, Multi-center, Dose-escalation Study to Assess the Safety, Tolerability and Pharmacokinetics of Orally Administered CUDC-907, a PI3K and HDAC Inhibitor, in Subjects With Refractory or Relapsed Lymphoma or Multiple Myeloma
This is a Phase I, open-label, multi-center dose-escalation trial evaluating the safety and
tolerability of CUDC-907 as a single agent administered orally, once daily, to patients with
relapsed or refractory lymphoma or multiple myeloma. The following dosing schedules may be
examined, all consisting of 21-day cycles and including:
(i) continuous once daily (QD), (ii) twice weekly on Days 1, 4, 8, 11, 15, 18 (BIW) (iii)
thrice weekly on Days 1, 3, 5, 8, 10, 12, 15, 17, 19 (TIW) (iv) four days on/three days off
on Days 1-4, 8-11, and 15-18 (4/3), and (v) five days on/two days off on Days 1-5, 8-12, and
15-19 (5/2)
Sequential dose escalation cohorts of oral CUDC-907 are planned. Subject enrollment and dose
escalation will proceed according to a standard 3+3 design. In the absence of DLT, each
subject will be treated for a minimum of 21 days, and may continue to receive additional
treatment until disease progression has been documented or other treatment discontinuation
criteria have been met.
MTD or BED expansion cohorts of up to 36 evaluable (e.g., up to 12 subjects in each of 2 or
3 specific tumor types or subtype) to better define the safety, tolerability and preliminary
antitumor and pharmacodynamic activity of the study treatment, as well as suitability as an
RP2D and schedule.
Safety and tolerability will be assessed by the incidence and severity of adverse events as
determined by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events
(CTCAE v4.03). A Safety Review Committee (SRC) comprised of the Medical Monitor, Principal
Investigators, and Sponsor representatives, will be convened to review safety information
and to decide upon dose escalation and further subject enrollment.
The antitumor activity of study treatment will be assessed according to standard response
criteria as appropriate for each individual subject's tumor type (e.g., Revised Response
Criteria for Malignant Lymphoma and the International Uniform Response Criteria for Multiple
Myeloma).
Exploratory biological markers of activity will be assessed in peripheral blood mononuclear
cells (PBMC), plasma and tissue specimens (skin, tumor and bone marrow samples, where
available).