Objective of the phase II POP study:To determine the safety and preliminary anti-tumor activity of AZD1775 in combination with carboplatin in p53 mutated epithelial ovarian cancer in a 21 day schedule.Objectives of the additional safety and…
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Brief title
Condition
- Reproductive neoplasms female benign
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Proof of concept trial:
To determine the safety and preliminary anti-tumor activity of MK-1775 in
combination with carboplatin in p53 mutated epithelial ovarian cancer in a 21
day schedule.
Additional safety and preliminary activity cohorts:
To determine the safety and preliminary anti-tumor activity (RECIST 1.1) of
AZD1775 in combination with carboplatin in p53 mutated epithelial ovarian
cancer, NSCLC, SCLC, cervical, and endometrial cancer, in a 21 day schedule
Secondary outcome
Phase II POP trial:
- To determine the pharmacokinetics of MK-1775 in plasma and of carboplatin in
plasma and ultrafiltrates.
- To determine pharmacodynamic changes induced by MK-1775 in combination with
carboplatin in both surrogate tissues (skin) and tumor tissue.
Additional safety and preliminary activity cohorts:
- To determine the time to progression.
- To determine the pharmacodynamic changes induced by AZD1775 in combination
with carboplatin in circulating tumor cells (CTC).
Background summary
Platinum-based drugs are used in first line treatment of epithelial ovarian
cancer. Despite high overall initial response rates, resistance or early
relapse can occur. MK-1775 is a potent and selective inhibitor of Wee-1 kinase,
a kinase that regulates the G2/M checkpoint. Since most human cancers retain
p53-related G1 checkpoint abnormalities, they are dependent on the G2
checkpoint. Annulment of the G2 checkpoint may therefore make p53 deficient
tumor cells more susceptible to anti-cancer agents. Therefore only patients
with established p53 mutated pathway that have shown early relapse (< 3 months)
or recurrence during standard platinum based treatment will be eligible for
this proof-of-concept trial and receive carboplatin in combination with
AZD1775.
As of 21 November 2016, this phase I study has been finished and reported(2). A
total of 202 patients were enrolled. Monotherapy AZD1775 was well tolerated and
the maximum tolerated dose (MTD) was not reached. The MTDs and biologically
effective doses were established for AZD1775 combined with each combination. Of
the 176 patients evaluable for efficacy, 94 (53%) had stable disease as best
response, and 17 patients (10%) achieved a partial response. AZD1775 was safe
and tolerable as single agent and in combination with chemotherapy at doses
associated with target engagement. In addition to this first-in-human phase I
study, a proof-of-concept phase II study was conducted in patients with
platinum refractory or early relapsed (<3 months) ovarian cancer. Results show
promising anti-tumor effects with an ORR of 43% (95%- confidence interval (CI),
22-66%), including 1 patient with a prolonged complete response. It
demonstrated manageable toxicity with fatigue (87%), nausea (78%),
thrombocytopenia (70%), diarrhea (70%) and vomiting (48%) as most common
adverse events (1).
Study objective
Objective of the phase II POP study:
To determine the safety and preliminary anti-tumor activity of AZD1775 in
combination with carboplatin in p53 mutated epithelial ovarian cancer in a 21
day schedule.
Objectives of the additional safety and preliminary activity cohorts:
To determine the safety and preliminary anti-tumor activity (RECIST 1.1) of
AZD1775 in combination with carboplatin in p53 mutated epithelial ovarian
cancer, NSCLC, SCLC, cervical, and endometrial cancer, in a 21 day schedule
Study design
Study design POP trial:
This study is a multi-center, open label, single arm phase II and
pharmacological study with carboplatin in combination with MK-1775 administered
as second-line therapy to patients with p53 mutated epithelial ovarian cancer
that show relapse or progression after standard first line treatment with
carboplatin - paclitaxel combination therapy. Carboplatin will be administered
at a dose resulting in AUC 5. The safe and tolerable dose of MK-1775 is
currently being established in a phase I study with MK-1775(MK1775-001: EudraCT
No. 2009-017054-12 / NL20803.031.07 - NKI M07MKC).
Each treatment cycle consists of 21 days. At day 1 of each cycle, carboplatin
(AUC 5) will be administered in a 30 min infusion. MK-1775 will be administered
as capsules BID for two and a half days starting concomitantly with each
administration of chemotherapy.
Eligible patients must have p53 mutated pathway determined by IHC at the
participating hospitals according to specific guidelines provided by the NKI
and with second review of digitally uploaded images in the central database by
pathologists of the NKI. Sequencing will also be performed at a later time
point at the NKI. (Additional tumor tissue will be sent to Roche for
retrospective concordance testing with AmpliChip p53 assay.) Patients must have
p53 mutated pathway confirmed by sequencing to be evaluable for the study.
Patients that have entered the study based on positive p53 by IHC, but which
cannot be confirmed by sequencing (negative for p53 mutation by sequencing) may
continue treatment, but will not be considered evaluable for the study.
A Simon two-stage design will be used whereby in the first stage (Step A) 18
eligible patients will be recruited. In case of sufficient response (evaluated
by RECIST or CA-125 levels), an additional cohort of 14 eligible patients will
be included in the second stage (Step B), to a total of 32 patients.
Study design additional safety and preliminary activity cohorts:
The additional safety and preliminary anti-tumor activity cohort is a
multi-center, open-label, non-randomized, single arm, cohort study in patients
with confirmed p53 mutated epithelial ovarian cancer, NSCLC, SCLC, cervical,
and endometrial cancer who previously received carboplatin and showed
recurrence on or within 6 months of this treatment. Patients are allowed to
have received second line treatment as well.
In the additional safety and preliminary anti-tumor activity cohort a minimum
of 10 patients will be recruited per tumor type. If no partial responses have
been documented in a defined tumor type that tumor type will be closed for
further recruitment. If at least one patient shows a PR, or better, recruitment
may continue until 29 patients have been included per tumor type.
Intervention
Treatment with carboplatin and Wee1 inhibitor AZD1775. Carboplatin will be
administered at a dose resulting in AUC 5. The safe and tolerable dose of
AZD1775 is currently being established in a phase I study with
AZD1775(MK1775-001: EudraCT No. 2009-017054-12 / NL20803.031.07 - NKI M07MKC).
Each treatment cycle consists of 21 days. At day 1 of each cycle, carboplatin
(AUC 5) will be administered in a 30 min infusion. AZD1775 will be administered
as capsules BID for two and a half days starting concomitantly with each
administration of chemotherapy. A dose of 225mg AZD1775 is found to be safe and
tolerable.
Study burden and risks
Patients participating may be hospitalized for about 2 days in the first week
of the first cycle, however this will depend on the individual study teams.
Blood for hematology, and serum chemistry (total for cycle 1: approximately 100
mL) will be drawn. The patient will undergo a physical exam and will have to
visit the hospital (or be contacted by the hospital) once every week.
Patients are at risk for carboplatin related side effects.
Plesmanlaan 121
Amsterdam 1066CX
NL
Plesmanlaan 121
Amsterdam 1066CX
NL
Listed location countries
Age
Inclusion criteria
Inclusion criteria for phase II POP trial:
1. p53 mutated (determined by IHC and later by sequencing) epithelial ovarian cancer
2. measurable disease on CT scan or elevated CA-125 levels that can be monitored
3. patients previously received standard 1st line platinum therapy (combined with paclitaxel) for epithelial ovarian cancer, and showed recurrence on or within 3 months of this treatment
4. age > 18 years
5. WHO performance status lower or equal to 1;Additional inclusion criteria for the safety and activity cohort:
1. histological or cytological proof of advanced epithelial ovarian cancer, NSCLC, SCLC, cervical and endometrial cancer (with proven p53 mutation).
2. previously treated with (standard) (1st) line platinum-based therapy (, and showed recurrence on or within 6 months after the end of this treatment.;3. Patients are allowed to have received second line non-platinum containing therapy after recurrence on 1st line treatment. No more than 2 lines of pre-treatment with cytotoxic chemotherapy are allowed.
4. Eligible patients will have p53 mutation determined by sequencing of exons 2-10. See chapter 10 for additional information and Appendix XI +XII
5. Able and willing to undergo a fresh tumor biopsy (if p53 status is already known , tumor biopsy is still mandatory) .
Exclusion criteria
1. symptomatic cerebral or leptomeningeal metastases
2. current participation or previous participation in a study with an investigational compound, or chemo- and/or radiotherapy within 28 days of receiving first dose of study medication
3. patient must not have prior radiation therapy to more than 30% of the bone marrow and must have recovered for at least 3 weeks from the hematologic toxicity of prior radiotherapy.
4. more than 2 prior cytotoxic chemotherapy regimens
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 | EUCTR2010-019106-16-NL |
| ClinicalTrials.gov | NCT01164995 |
| CCMO | NL31685.031.10 |