Primary objective:the primary objective of the study is to evaluate the safety and to define the maximal tolerated dose or the maximal administered dose of CC-486 as a single agent, in combination with CBDCA or ABI-007 in subjects with relapsed or…
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Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
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Intervention
Outcome measures
Primary outcome
The nature, incidence and severity of AEs will be evaluated using the National
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)
criteria, Version 4.0.
Secondary outcome
For CC-486 (administered alone and in combination), CBDCA, ABI-007 , the
following plasma PK parameters will be assessed:
* maximum observed concentration in plasma (Cmax);
* area under the concentration-time curve (AUC);
* time to maximum concentration (tmax);
* terminal half-life (t1/2);
* apparent total body clearance (CL/F); and,
* apparent volume of distribution (Vz/F).
To evaluate the PD effects of CC-486 in blood, plasma, and tumor tissue, the
following molecular characterizations will be performed;
* Change from baseline (Cycle 1 Day 1 pre-dose) in DNA methylation (global and
gene-specific assays) in whole blood and tumor
tissue (as available in Part 1); and,
* Reduction from baseline (Cycle 1 Day 1 predose) in DNMT1 protein levels in
tumor tissue (as available in Part 1).
Anti-tumor activity endpoints using tumor-specific response criteria for each
tumor type will include:
* Response rate and duration of response;
* Progression-free survival (PFS); and,
* See definition of response in statistical analysis section.
Exploratory Endpoints - CC-486 Response
Molecular characteristics of the blood and tumor, potentially including, but
not limited to, DNA/RNA methylation, gene sequence and mRNA/miRNA expression
may be evaluated at baseline and post-therapy for examination in relation to
tumor responses.
Background summary
The hypothesis underlying the combination of a DNA hypomethylating agent with
Standard of Care (SoC) cytotoxic chemotherapy is that methylation-based
silencing of specific genes limits the anti-tumor effects of cytotoxic agents.
Testing this hypothesis rigorously will ultimately require a randomized trial
of a SoC agent versus that agent combined with CC-486. The long term goal of
the current study is to enable such a study by identifying a dose and schedule
of CC-486 that can be safely administered with a cytotoxic agent and that
consistently demonstrates pharmacologic activity. Pre-clinical data suggest
that platins and taxanes are 2 classes of SoC cytotoxic agents that synergize
with CC-486. By examining combinations with both agents each with its own
distinct single agent safety profile, this study increases the likelihood of
identifying at least one safe combination. If both combinations are found to be
safe, the divergent mechanisms of action of CBDCA and ABI-007 and Gemcitabine
increase the spectrum of tumor types that can be explored for activity.
Finally, a single-agent Arm will enable the testing of the hypothesis that
sustained daily dosing of CC-486 can have anti-tumor effects in specific tumor
types. Since a continuous dosing schedule has not been explored in the AZA PH
US 2007 CL 005 CC-486 study, the current study will determine whether such a
schedule is tolerated by subjects with solid tumors.
Study objective
Primary objective:
the primary objective of the study is to evaluate the safety and to define the
maximal tolerated dose or the maximal administered dose of CC-486 as a single
agent, in combination with CBDCA or ABI-007 in subjects with relapsed or
refractory solid tumors
Secondary objectives:
* to examine the impact (if any) of CBDCA or ABI-007 on the pharmacokinetics
(PK) of CC-486;
* to examine the impact (if any) of CC-486 on the PK of CBDCA or ABI-007
* to evaluate the pharmacodynamic (PD) effects of CC-486 as a single agent and
in combination with CBDCA and ABI-007
* to make a preliminary assessment of the anti-tumor activity of CC-486 as a
single agent and in combination with CBDCA and ABI-007
Exploratory Objective:
The exploratory objective of the study is to determine whether there is any
relationship among baseline tumor molecular characteristics (genetic or
epigenetic), PD effects, and anti-tumor activity.
Study design
This will be a phase 1, open-label, 3-arm, multi-center dose-escalation study
of CC-486 in combination with CBDCA (Arm A) or ABI-007 (Arm B), or as a single
agent (Arm C) in subjects with relapsed or refractory solid tumors (Part 1),
followed by expansion cohorts at the Recommended Part 2 Dose (RP2D) of CC-486
in specific tumor types in Part 2.
In part 2, expansion cohorts of up to 20 subjects for each of the following
relapsed or refractory tumor types will be enrolled at the RP2D for each Arm:
*Arm A: CC-486 plus CBDCA:
- urothelial carcinoma of the bladder, renal pelvis, ureter, or urethra (mixed
histologies are permitted provided
a component of urothelial carcinoma is present)
- epithelial ovarian, fallopian tube, or primary peritoneal carcinoma
*Arm B: CC-486 plus ABI-007:
- NSCLC
- Pancreatic carcinoma
*Arm C: CC-486 single agent
- Virally associated tumors (tumor types known to be driven by Epstein-Barr
virus, Human Papilloma Virus (HPV) and Merkel cell
carcinoma of the skin (MC polomavirus):
- Nasopharyngeal carcinoma (a minimum of 5 subjects)
- Cervical carcinoma
- Anal carcinoma
- Merkel cell carcinioma (MCc)
Note: hepatitis B virus (HBV) and hepatitis C virus
(HCV) -associated tumors (hepatocellular cancers) are not eligible.
Note: head and neck squamous cell cancers (HNSCC) must
have HPV-positive status documented to be eligible.
Subjects in Part 2 of the study will receive CC-486 alone (Arm C) or in
combination with CBDCA (Arm A) or ABI-007 (Arm B) according to the RP2D
established for each Arm in Part 1. All treatment Cycles in Part 2 will be 21
days in duration.
Intervention
Subjects enrolled in the study will be assigned treatment as outlined by the
following relapsed or refractory tumor types:
* CC-486 plus carboplatin (CBDCA) (Arm A):
* Urothelial carcinoma of the bladder, renal pelvis, ureter, or urethra (mixed
histologies are permitted provided a component of urothelial carcinoma is
present)
* Epithelial ovarian, fallopian tube, or primary peritoneal carcinoma
* CC-486 plus ABI-007 (arm B)
* NSCLC
* Pancreatic carcinoma
* CC-486 as a single agent (Arm C):
* Virally associated tumors (tumor types known to be driven by Epstein-Barr
virus, Human Papilloma Virus (HPV) and Merkel cell carcinoma of the skin (MC
polomavirus):
- Nasopharyngeal carcinoma (a minimum of 5 subjects)
- Cervical carcinoma
- Anal carcinoma
- Merkel cell carcinioma (MCc)
Note: hepatitis B virus (HBV) and hepatitis C virus (HCV) -associated tumors
(hepatocellular cancers) are not eligible.
Note: head and neck squamous cell cancers (HNSCC) must have HPV-positive status
documented to be eligible.
All cycles in arm A, B and C are 21 days in duration. In arm D, the first cycle
is 22 days in duration, all other cycles are 21 days.
Arm A patients take CC-486 orally on day 1-14 and receive CBDCA as an iv
infusion over 1 hour on day 8 of each cycle
Arm B patients take CC-486 orally on day 1-14 and receive ABI-007 as an iv
infusion over 30 minutes on day 8 and day 15 of each cycle
Arm C patients take CC-486 orally on day 1-14 of each cycle
Study burden and risks
- Patients have to complete a diary in which they write down for example the
time of medication intake.
- Patients will come to the hospital 3 x per cycle
- During visits, physical examination is performed.
- During the study an ECG is done 3x
- The patient has to be fasting on PK days 2 hours before and 2 hours after
CC-486 intake
- There are pregnancy tests for women of childbearing potential
- Patients have to use anticonception which is approved by the study doctor
- Blooddraws on day 1 and 15 of every cycle (in cycle 1 also on day 8) of about
15 ml
- On PK days (cycle 1, day 1 and 8, and on day 1 of cycle 2,3 and 6) 2
bloodsamples will be taken of about 5 ml each
-- On PD days (cycle 1 day 1,8 and 15 and on day 1 of cycle 2,3 and 6) about 60
to 70 ml of blood will be taken (2 times 8.5 ml paxgene and 4 times 10 ml
biomarkers).
- if the dosis of CC-486 is reduced , there will be 2 extra PK samples and 1
extra PD sample (in total about 30 ml)
- The tumor is measured using scans at screening, cycle 2,4 6 and every 3rd
cycle after that
- ABI-007 and Carboplatine are administered via an iv infusion
- There will be a tumorbiopsy twice
Winthontlaan 2
Utrecht 3526 KV
NL
Winthontlaan 2
Utrecht 3526 KV
NL
Listed location countries
Age
Inclusion criteria
1.Men and women, 18 years or older
2. Understand and voluntarily sign an ICD prior to any study-related assessments or procedures are conducted
3. Able to adhere to the study visit schedule and other protocol requirements
4. Histological or cytological confirmation of relapsed or refractory advanced unresectable solid tumors as listed below for each Arm, including those who have progressed on (or not been able to tolerate) standard anti-cancer therapy
* Arm A: CC-486 plus CBDCA:
- Urothelial carcinoma of the bladder, renal pelvis, ureter, or urethra (mixed histologies are permitted provided a component of urothelial carcinoma is present)
- Epithelial ovarian, fallopian tube, or primary peritoneal carcinoma
* Arm B: CC-486 plus ABI-007:
- NSCLC
- Pancreatic carcinoma
* Arm C: CC-486 as a single agent:
- Virally associated tumors (tumor types known to be driven by Epstein-Barr virus,
Human Papilloma Virus (HPV) and Merkel cell carcinoma of the skin (MC
polomavirus):
- Nasopharyngeal carcinoma (a minimum of 5 subjects)
- cervical carcinoma
- Anal carcinoma
- Merkel cell carcinioma (MCc)
Note: hepatitis B virus (HBV) and hepatitis C virus (HCV) -associated tumors
(hepatocellular cancers) are not eligible.
Note: head and neck squamous cell cancers (HNSCC) must have HPV-positive
status documented to be eligible.
5. Consent to screening tumor biopsy (prior to the first dose of CC-486) and at cycle 1 day 15
6. Eastern Cooperative Oncology Group (ECOG) Performance Status of * 2.
7. Absolute neutrophil count (ANC) * 1.5 x 109/L;
Hemoglobin (Hgb) * 90 g/L;
Platelets (plt) * 100 x 109/L;
Potassium within normal range, or correctable with supplements;
AST and ALT * 2.5 x Upper Limit of Normal (ULN) or * 5.0 x ULN if liver tumor is present;
Serum total bilirubin * 1.5 x ULN;
Serum creatinine * 1.5 x ULN, or 24-hr clearance * 60 mL/min; and,
Negative serum pregnancy test within 72 hours before starting study treatment in females of
childbearing potential (FCBP).
8. Females of child-bearing potential (defined as a sexually mature woman who 1) has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or, 2) has not been naturally postmenopausal for at least 24 consecutive months (ie, has had menses at any time during the preceding 24 consecutive months).must:
* Agree to the use of a physician-approved contraceptive method (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) while on CC-486; and for 3 months following the last dose of study medication; and
* Have a medically supervised serum pregnancy test with sensitivity of at least 25mIU/mL is to be obtained in FCBP at Screening. A serum pregnancy test should be done within 72 hours prior to Day 1 of starting study therapy (note that the screening serum pregnancy test can be used as the test prior to Day 1 study therapy if it is performed within the 72-hour timeframe). A serum pregnancy test should be done within 72 hours prior to Day 1 of every cycle, and at the Treatment Discontinuation visit. The subject may not receive investigational product until the investigator has verified that the result of the pregnancy test is negative.
9. Male subjects with a female partner of childbearing potential must agree to the use of a physician-approved contraceptive method throughout the course of the study and avoid fathering a child during the course of the study and for 6 months following the last dose of CC-486.
10. Subjects with documented liver metastases must have serum albumin * 3 g/dL;
11.Sites of disease (primary or metastatic) that are, in the opinion of the investigator, accessible for biopsy without undue risk to the subject
12.Measurable or evaluable disease according to RECIST v1.1.
Exclusion criteria
1. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
2. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
3. Any condition that confounds the ability to interpret data from the study.
4. Symptomatic central nervous system metastases. Subjects with brain metastases that have been previously treated and are stable for 6 weeks are allowed.
5. Known acute or chronic pancreatitis.
6. Any peripheral neuropathy * NCI CTCAE grade 2.
7. Persistent diarrhea or malabsorption * NCI CTCAE grade 2, despite medical management.
8. Impaired ability to swallow oral medication.
9. Unstable angina, significant cardiac arrhythmia, or New York Heart Association (NYHA) class 3 or 4 congestive heart failure.
10. Prior systemic cancer-directed treatments or investigational modalities * 5 half lives or 4 weeks, whichever is shorter, prior to starting study drug or who have not recovered from side effects of such therapy.(except alopecia).
11. Major surgery * 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy.
12. Pregnant or breast feeding.
13. Known HIV infection.
14. Known chronic hepatitis B or C virus (HBV/HCV) infection, unless this is a comorbidity in subjects with HCC.
15. Liver metastases with serum albumin lower or equal to 3 g/dL.
16. Other prior cancers within previous 5 years except adequately treated in situ carcinoma cervix, basal or squamous carcinoma of the skin.
17. Subjects with >4 prior systemic chemotherapy regimens will require approval by the Celgene medical monitor prior to enrollment.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-001295-11-NL |
| CCMO | NL42064.031.12 |