Download Diapositiva 1

MITO 29
Randomized Phase II study on
Decitabine plus Carboplatin versus
physician’s choice chemotherapy in
recurrent, platinum-resistant
ovarian cancer
Study design
II line chemotherapy
(physician choice):
N= 132
- Recurrent,
platinum resistant
(no refractory)
epithelial ovarian,
Fallopian tube,
primary Peritoneal
cancer
- No more than 2
previous CHT lines
Evaluable or Measurable
disease
R
A
N
D
O
M
I
Z
A
T
I
O
N
- PLD 40 mg/mq d1 q28;
- Weekly Paclitaxel 80 mg/mq d1,8,15 q28
- Gemcitabine 1000 mg/mq gg1,8,15 q28
II line chemotherapy
(physician choice):
- Carboplatin AUC 5 d8 + Decitabine 10
mg/mq iv d1-5 q 28
Random1.1
MITO 27
Rationale
Recently, it has become clear that tumors can be driven by patterns of altered gene
expression that are mediated by mechanisms of epigenetic regulation, such as DNA
methylation.
DNA demethylation has the potential to reverse promoter hypermethylation in tumor
cells and lead to the reexpression of aberrantly silenced genes, such as tumor
suppressor genes (TSGs) and to induce the sensitivity of tumor cell to anticancer
agents.
Decitabine (5-aza-2’-deoxycytidine, DACOGEN) is a cytidine nucleoside analog with
a proposed epigenetic mechanism of action; hypomethylation of DNA. Inhibition of
cytosine methylation by decitabine has been shown to correlate with the reexpression of silenced genes and, in tumor cells the re-expression of tumor
suppressor gene products.
In 2006, DACOGEN (DAC) was approved in the United States for use in patients
with myelodysplastic syndromes (MDS).
MITO 29
Rationale
•
•
•
•
Decitabine has been reported to inactivate DNA methyltransferases (DNMTs) by forming a
covalent complex at CpG methylation sites.
Additionally, preclinical data suggest that DAC can significantly reverse the expressions of
genes that are differentially regulated at the relapse stage, and some of these genes may
play a role in chemoresistance .
DAC has also been proposed to possess immunomodulatory activity that is mediated by
the restoration of the proper expression of immune receptors and their ligands. The
epigenetic remodeling induced by DAC has been suggested to enhance tumor
immunogenicity and tumor susceptibility to immune destruction by upregulating the
expression of tumor antigens and major histocompatibility complex (MHC) class I in
cancers .
Several preclinical studies of ovarian cancer have indicated that hypomethylating agents,
including the deoxycytidine analog decitabine, can reverse platinum resistance in
chemoresistant cancer cell lines and mouse-engrafted tumors (17-18).
Rationale for the dose
•
Fong et al in a phase I-II clinical trial reported that decitabine 10 mg/mq, administered dd 1-5 q28 in
combination with carboplatin AUC 5 d8 q 28, resulted in 35% RR in platinum-resistant OC patients and
9 of 17 treated patients (53%) were free of disease pogression at 6 months. Most common toxicities were
nausea, allergic reactions, neutropenia, fatigue, anorexia, vomiting, and abdominal pain, the majority
being grades 1-2.
•
Glasspol et al in a randomized trial on decitabine (90 mg/mq d1 q 28) plus carboplatin (AUC 6 d1 q 28)
vs carboplatin alone in 15 platinum sensitive recurrent ovarian cancer patients reported the lack of
efficacy and poor treatment tolerability for combination; responses by RECIST were 6 out of 13 vs 1 out
of 12 for carboplatin and carboplatin/decitabine, respectively. Grade 3/4 neutropenia was more common
with the combination (60% vs 15.4%) as was G2/3 carboplatin hypersensitivity (47% vs 21%).
The authors concluded that with this schedule, the addition of decitabine appears to reduce rather than
increase the efficacy of carboplatin in partially platinum-sensitive ovarian cancer and is difficult to
deliver and that different patient-selection strategies and different schedules should be considered in
future combination studies.
Objectives
Primary:
Progression free survival (PFS)
Secondary:
- Overall survival (OS)
- Radiological response rate (in patients with measurable disease)
- Duration of response
- CA-125 response rate per GCIG and change in CA-125
- Toxicity profile
- Quality of life will be evaluated using the FACT-O and FACT-O
ovarian cancer-specific subscale (OCS) questionnaire.
MITO 29
Inclusion Criteria
Cytologic / histologic diagnosis of stage IC-IV epithelial ovarian, fallopian tube or peritoneal cancer
(carcinosarcomas are included)
Disease relapsed within 1-6 months after the last platinum treatment
Disease measurable or evaluable by RECIST version 1.1 or Ca 125 GCIG criteria
No residual peripheral neurotoxicity > Grade 1 from previous chemotherapy treatment
PS 0-1
Age > 18 years.
Life expectancy of at least 3 months
Written informed consent prior to performance of study specific procedures or assessments
Ability and willingness to comply with treatment and follow up assessments and procedures
Adequate organ functions:
Hematopoietic: Leukocytes > 2,500/mm3; Absolute neutrophil count >1,500/mm3; Platelets count
>100,000/mm3; Hemoglobin >9 g/dL
Hepatic: AST and ALT <3 times upper limit of normal (ULN)*; Alkaline phosphatase <3 times ULN*;
Bilirubin <1.5 times ULN
*: <5 times ULN if liver metastases are present
Renal: Creatinine clearance >45 mL/min
No other invasive malignancy within the past 3 years except non-melanoma skin cancer and in situ
cervical cancer
Absence of any psychological, familial, sociological or geographical conditions potentially
hampering compliance with the study protocol and follow-up schedule.
Written informed consent.
MITO 29
Exclusion Criteria
More than two previous chemotherapy lines.
Pregnant (potentially fertile patients must use contraceptive measures to avoid pregnancy during and for at least 3
months after study participation and must have a negative serum
pregnancy test at baseline).
Patients should not be breast-feeding during treatment and for 2 months following the end of treatment.
Serious heart disease, including heart failure, atrio-ventricular block of any degree, serious arrhythmia or history of
any one or more of the following cardiovascular conditions within the past 6 months: cardiac angioplasty or stenting,
myocardial infarction, unstable angina, symptomatic peripheral vascular disease, coronary artery by-pass graft
surgery, class II, III or IV congestive heart failure as defined by the New York Heart Association (NYHA)
Active infection requiring antibiotics.
History of cerebrovascular accident, pulmonary embolism or untreated deep venous thrombosis (DVT) within the
past 6 months
History of human immunodeficiency virus (HIV) infection or chronic hepatitis B or C.
Patients who had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 4 weeks prior to
study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously
administered agent. Note: Subjects with < Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to this
criterion and may qualify for the study.
Patients with evidence of interstitial lung disease.
Major surgical procedure, open biopsy, or significant traumatic injury within 3 weeks prior to beginning therapy, or
anticipation of the need for a major surgical procedure during the course of the study; minor surgical procedures such
as fine needle aspiration or core biopsy within 1 week prior to beginning therapy are also excluded.
Known hypersensitivity to the study drugs or to drugs with similar chemical structures.
Concurrent treatment with other experimental drugs.
Participation in another clinical trial with any investigational drug within 30 days prior to study screening.
MITO 29
Statistical consideration
This is a randomize phase II trial. The sample size is based on the primary
efficacy endpoint, PFS.
Because of the nature of the study design, randomized phase II, relaxed
statistical parameters were used (one-sided alfa 0.10, beta 80%)
The required sample size was calculated assuming exponential distributions
and that a median PFS of 3 months from study drug administration would
be observed in the wPTX /PLD/GEM arm (control arm). Overall, 119 events
were needed to detect an improvement with Decitabine-Carboplatin
(experimental arm) in median PFS to 4.5 months, corresponding to a
hazard ratio (HR) of 0.65, based on a one-sided log-rank test at the error
alfa= .010 (one-sided) and a power of 80%. Expecting ~10% of censoring
rate ~132 patients will be necessary to get 119 events and supposing a
recruitment rate of 2.5 patients/week it is expected to complete the
recruitment in ~1,6 years.
MITO 29
Administrative Information
•Academic trial
•NCI of Milan sponsor
•Data center: NCI of Milan (MITO center)
•Planned study start: May 2017
• Assurance and Decitabina provided
•Jansen Cilag support: Decitabina and financial support for data management,
insurance and drug management
To participate please contact:
[email protected]
[email protected]
MITO 29