Primary Objective: * To make a preliminary assessment of the efficacy of a combined APR-246 and carboplatin/PLD chemotherapy regimen in patients with platinum sensitive recurrent HGSOC with mutated p53.Secondary Objective: * To assess the safety…
ID
Source
Brief title
Condition
- Reproductive neoplasms female malignant and unspecified
- Ovarian and fallopian tube disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoints
* Progression Free Survival (PFS), defined as the time from registration to the
time of disease progression or relapse (according to RECIST 1.1 only) or death,
or the date of last tumor assessment without any such event (censored
observation).
Secondary outcome
Secondary Endpoints
* PFS by assessment of CA 125 as a tumor marker.
* Overall Survival (OS), calculated as the time from registration to the date
of death from any cause.
* Overall Response Rate (RR), calculated as the proportion of patients with a
best overall response of confirmed Complete Response (CR) or Partial Response
(PR).
* Safety profile (AEs, laboratory assessments and physical findings) of the
combined APR-246 and carboplatin/PLD chemotherapy regimen or the
carboplatin/PLD chemotherapy regimen alone.
* Evaluation of potential biomarkers.
* Biological activity in tumor and surrogate tissues.
Background summary
High Grade Serous Ovarian Cancer (HGSOC) accounts for approximately 70% of
malignant surface epithelial carcinoma in Europe and North America. Clinical
data shows that p53 mutations are present in at least 96% of patients with
HGSOC. Furthermore, p53 mutations have been shown to correlate significantly
with resistance to chemotherapy, early relapse and shortened overall survival.
Despite the evolution of surgical techniques and ever improving chemotherapy
regimens, relapse and consequential disease progression remains the most
challenging task for ovarian cancer patients. The combination of carboplatin
and pegylated liposomal doxorubicin has shown a improvement in PFS (11.3 months
versus 9.4) with lower rates of severe and long-lasting side effects, and has
been accepted as European standard of care for patients with platinum-sensitive
ovarian cancer, including HGSOC.
APR-246 may offer an opportunity to improve current treatment of HGSOC. The
rationale for this derives from preclinical evidence that APR-246/MQ (i.e., the
active moiety of APR-246) induces apoptosis and cell death in cancer cells with
mutant or otherwise non-functional p53. Additional to the apoptosis-inducing
effect as a single substance, APR-246 can act synergistically with platinum
compounds by reversing the cisplatin sensitivity of cisplatin-resistant p53
mutant ovarian cancer cell lines, resulting in resensitization of cancer cells
to cisplatin.
Study objective
Primary Objective:
* To make a preliminary assessment of the efficacy of a combined APR-246 and
carboplatin/PLD chemotherapy regimen in patients with platinum sensitive
recurrent HGSOC with mutated p53.
Secondary Objective:
* To assess the safety profile of the combined APR-246 and carboplatin/PLD
chemotherapy regimen compared with carboplatin/PLD chemotherapy regimen alone.
* To evaluate potential biomarkers.
* To assess the biological activity in tumor and surrogate tissues.
Study design
This study is an open-label, multi-center Phase Ib/II proof-of-concept study
with a dose confirmation component to assess whether patients with platinum
sensitive recurrent p53 mutated HGSOC will benefit from treatment with APR-246
in combination with a carboplatin/PLD chemotherapy regimen. It is planned that
patients will receive up to 6 cycles of treatment.
All patients will have pre-screening IHC to determine p53 status and therefore
eligibility. Archived sections from the original tumor sample will be reviewed
by a gynecological pathologist to confirm the diagnosis of high grade serous
ovarian cancer and positive nuclear IHC staining for p53. Patients without
positive nuclear p53 staining will not be included.
Patients will be randomly assigned in a 1:1 ratio to receive either:
* Arm A: APR-246 with the carboplatin/PLD chemotherapy regimen,
* Arm B: Carboplatin/PLD chemotherapy alone.
The Phase II will enroll 164 evaluable patients with p53 mutation. CT/MRI
measurements using RECIST 1.1 criteria will be performed at Pre-treatment,
after 2 cycles (8 weeks), 4 cycles (16 weeks) and after the last cycle (24
weeks).
At subsequent follow-up visits tumor assessments should only be performed if
clinical symptoms are suggestive of recurrence or there is CA 125 progression
as defined by GCIG criteria (Rustin et al., 2011). Radiological tumor
assessment should occur within 3 weeks of the date of suspected clinical or CA
125 progression. If there is CA 125 progression but no radiological
documentation of disease progression then imaging should be repeated at least
3-monthly until protocol defined progression occurs. For patients with stable
disease, follow-up will take place until disease progression or until death.
All scans should have the same modality (CT or MRI) but CT is preferred.
Intervention
Intravenous infusion with APR-246 (dose tbc) on days 1-4 of each cycle. Maximum
6 cycles.
Intravenous infusion with Carboplatin (AUC 5) and Caelyx (30 mg/m2) on day 4 of
each cycle. Maximum 6 cycles.
Study burden and risks
In the completed Phase I clinical trial (APR-246-01) only a relatively few
reported AEs (adverse events) were considered to be potentially related to
treatment. From patients who received the 2-hour infusion of APR246 the most
common related AEs related were fatigue, followed by dizziness, headache, and
confusion and other neurologic AEs such as muscle spasms and sensory
disturbances. The treatment*related AEs typically occurred at the end of the
infusion or shortly after the infusion and continued for hours or, in some
cases, days. All AEs were reversible. No bone marrow toxicity was seen.
In a subsequent amendment to that study (Amendment 6), the duration of study
drug administration was increased to be a 6-hour infusion to attempt to reduce
and minimise the neurological AEs previously seen. Considering the patients*
advanced disease, good tolerability was demonstrated. The number of reported
AEs was limited and most events were considered as unlikely related to the
APR-246 treatment. The AEs judged to have possible or probable relationship to
the study treatment were single reports of dizziness, dyskinesia (Nervous
system disorders), disorientation (Psychiatric disorders), fatigue (General
disorders), electrocardiogram QT prolonged (Investigations) and osteonecrosis
(Muscular and connective diseases).Two of these events, dyskinesia and
electrocardiogram QT prolonged, reported by the same patient, were judged to be
serious, related to the APR-246 treatment and not previously described or
expected (i.e., SUSARs). Overall, APR-246 was well tolerated and with a safety
profile very different from conventional chemotherapies.
A secondary centralized analysis of the ECGs collected from patients enrolled
under Amendment 6 was done by a central laboratory. It concluded that there do
not appear to be consistent, systematic, individual ECG changes after exposure
to APR-246. Nonetheless, a small effect of APR-246 on the QTcF interval cannot
be ruled out given the quality of the ECG database, and collection of digital
ECG in triplicate format in a further trial is intended. A robust cardiac
monitoring was therefore instigated in the Phase Ib part of the current,
ongoing study in cycle 1. This included 12-lead ECG performed at baseline, Day
19 cycle 1 and before all other treatment cycles. The patients also have a 24
hour Holter ECG on Days 1 and 4 of APR-246 infusion for the first cycle. This
data will is centrally analysed by Cardiabase and also reviewed by the Cohort
Review Committee (CRC). This data has demonstrated that in Cohorts 1 and 2
there is no evidence of cardiac toxicity.
In line with the directive on risk mitigation (EMEA/CHMP/SWP/28367/07) the
design of the trial takes into consideration possible unanticipated effects of
APR-246 together with concomitant administration of carboplatin/PLD and, in the
currently ongoing Phase Ib part of the study, a safety evaluation was performed
by the treating investigator prior to each dosing within a cohort. The second
and third cohorts were not initiated until all of the patients in the first
cohort had been reviewed by the CRC.
The clinical data reviewed to date in the ongoing Phase Ib part of the study
confirms that the nervous and the gastrointestinal systems are main potential
target organs for toxicity. The treatment*related AEs typically occurred at the
end of the infusion or shortly after the infusion and continued for hours or,
in some cases, days. All AEs were reversible. The early evolving data from the
APR-407 study seems to suggest that APR-246 may potentiate the bone marrow
suppression caused by chemotherapy. This finding is still under evaluation and
will likely be clarified only in the randomised part of the study.
To date, the most frequently reported adverse events (regardless of severity)
related to APR-246 study drug include fatigue, nausea, vomiting, dizziness,
headache and taste changes. These events were also reported in the previous
clinical trials as effects related to APR-246 monotherapy treatment.
Haematological events (neutropenia, thrombocytopenia), and low grade CNS
related effects (dizziness, vertigo, nausea, dysgeusia) have also been
reported. No new safety concerns have emerged.
To date, patients have been enrolled in all three dose cohorts of the Phase Ib
part of the study and the patients in the first cohort have completed therapy.
In cohort 1, 2 patients were partially platinum sensitive and 1 sensitive. At
least 5 patients have tolerated 6 cycles of treatment. One dose-limiting
toxicity (DLT) of ruptured diverticulum has been reported (patient 004 in
Cohort 2). This led to the expansion of this cohort to 6 patients.
Several patients in the current study have experienced neutropenia and
thrombocytopenia, often requiring GCSF support in order to be able to continue
with APR-246 and carboplatin/PLD treatment. Many patients experienced delays
and/or dose reductions due to myelosuppression. No bone marrow toxicities were
noted in the previous clinical studies with single agent APR 246.
Myelosuppression is associated with carboplatin/PLD. It is too early to
determine whether or not the severity of myelosuppression is increased with
combination of APR-246 and carboplatin/PLD.
A single patient experienced a single episode of temporarily elevated hepatic
enzymes; therefore, a safety update was distributed to all investigational
sites. This was to advise caution when co-administrating APR-246 and full dose
paracetamol (i.e. 4g/24hrs) based compounds, and that such compounds should be
immediately terminated if any increase from baseline liver function tests were
detected. The patient information sheets were also revised to include this
theoretical risk.
The risks associated with drawing blood may include momentary discomfort and
bruising. In rare cases, infection, excess bleeding, clotting or fainting may
occur. The risks associated with biopsy may include numbness or tingling where
the local anaesthesia is applied, temporary pressure and/or pain during the
procedure, bleeding, bruising or soreness at the site after the sample is
collected. Rarely, infection can develop. These effects, should they occur,
will be managed per local hospital guidelines.
All patients will have their haematological, biochemical, vital signs and ECG
parameters monitored. The eligibility criteria place more stringent than normal
limitations on platelet count, white cell and especially lymphocyte count, AST
and ALT levels, bilirubin and albumin. Events considered possibly related to
APR-246 will be evaluated and any appropriate changes to trial procedures or
monitoring will be instituted.
The investigation of APR-246 in combination with carboplatin/PLD in this
patient population is justified, based upon the clinical and nonclinical safety
profile, the limitations of current treatments available to patients, the
limited life expectancy due to malignant disease, and the strength of the
scientific hypothesis under evaluation. Thus the benefit/risk assessment for
this study supports the administration of APR-246 to patients with platinum
sensitive, recurrent p53 mutated HGSOC to increase the efficacy of the platin
based combination chemotherapy treatment.
Expected benefit:
The previous phase I study in patients demonstrated both the feasibility of
administering potentially effective doses of APR-246 to humans and suggested
APR-246 has a favourable safety profile compared with current cytotoxic
therapies in practice. APR-246 exhibits linear pharmacokinetics up to the
dosages administered. In patients, plasma concentrations consistently above
those associated with effects in both ex vivo and in vivo pre-clinical models
have been achieved. Thus, the feasibility of administering potentially
effective doses of APR-246 in humans has been demonstrated.
Mutated p53 is a hallmark of HGSOC and correlates significantly with resistance
to chemotherapy, early relapse and shortened overall survival. There is
therefore a need for improved treatment of HGSOC since currently available
therapies have little impact on survival. APR-246 may offer such an opportunity
since p53 mutation is found in at least 90% of patients with late stage HGSOC
(stage III * IV) at the time of diagnosis. APR-246 has been shown to induce
apoptosis and cell death in cancer cells with mutant or otherwise
non-functional p53 and has strong synergistic anticancer effects in combination
with several conventional chemotherapeutic drugs including platinum-containing
agents.
Karolinska Institutet Science Park, Nobels väg 3
Solna SE-171 65
SE
Karolinska Institutet Science Park, Nobels väg 3
Solna SE-171 65
SE
Listed location countries
Age
Inclusion criteria
1. Archived sections from the original FFPE sample reviewed by a gynecological pathologist confirming High Grade Serous Ovarian Cancer, High Grade Serous Peritoneal Cancer or Primary Fallopian Tube Cancer, and positive IHC staining for p53 assessed according to defined standard (as detailed in the laboratory manual). Cases that do not show p53 staining will not be included.
2. Radiologically-confirmed Disease Progression between six and twenty-four (6-24) months after a first or second platinum based regimen.
3. At least a single (RECIST v1.1) measurable lesion.
4. Adequate organ function prior to registration:
a) Bone Marrow Reserve:
* Absolute neutrophil count (ANC) * 1.5 x109/L,
* Platelets * 100 x109/L,
* Hemoglobin * 9 g/dL.
b) Hepatic:
* Total bilirubin level < 1.5 x ULN,
* ALT and AST < 2.5 x ULN.
c) Renal:
* Calculated creatinine clearance > 30 mL/min.
d) Electrolytes
* Potassium within institutional normal ranges.
5. Toxicities from previous cancer therapies, excluding alopecia, must have recovered to grade 1 (defined by CTCAE version 4.0). Chronic stable grade 2 peripheral neuropathy secondary to neurotoxicity from prior therapies may be considered on a case by case basis by the Principal Investigator.
6. If of childbearing potential, negative pre-treatment serum pregnancy test.
7. If of childbearing potential, willing to use an effective form of contraception (see below) during
chemotherapy treatment and for at least six months thereafter. Such methods include: (if using hormonal contraception this method must be supplemented with a barrier
method, preferably male condom).
* Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
o Oral
o Intravaginal
o Transdermal ;* Progestogen-only hormonal contraception associated with inhibition of ovulation:
o Oral
o Injectable
o Implantable
* Intrauterine device (IUD)
* Intrauterine hormone-releasing system (IUS)
* Bilateral tubal occlusion
* Vasectomized partner
* True sexual abstinence when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception.
* Male condom with spermicide (female condom and male condom should not be used together)
8. ECOG performance status of 0 to 1 (Appendix I).
9. * 18 years of age.
10. Written informed consent obtained prior to any screening procedures and in accordance with federal, local, and institutional guidelines.
11. Patient has exhausted all available treatments, including surgery, and is considered a suitable candidate to receive carboplatin/PLD.
Exclusion criteria
1. Prior exposure to cumulative doses of doxorubicin >400 mg/m2 or epirubicin >720 mg/m2.
2. Confirmed cardiac history of any of the following:
a) Myocardial infarct within six months prior to registration,
b) New York Heart Association Class II or worse heart failure (Appendix II),
c) A history of familial long QT syndrome,
d) Clinically significant pericardial disease,
e) Electrocardiographic evidence of acute ischemia,
f) Symptomatic atrial or ventricular arrhythmias not controlled by medications,
g) QTc * 480 msec calculated from a single ECG reading or a mean of 3 ECG readings using
Fridericia*s correction (QTcF = QT/RR0.33),
h) Bradycardia (< 40bpm),
i) Left ventricular ejection fraction (LVEF) < the institution lower limit of normal as assessed by ECHO.
3. Major abdominal surgery or peritonitis within six weeks prior to study treatment.
4. Unresolved bowel obstruction, sub-occlusive disease or the presence of brain metastases.
5. History of uncontrolled allergic reactions to carboplatin, platinum containing compounds or mannitol and/or hypersensitivity to PLD or to any of the excipients.
6. Unable to undergo imaging by either CT scan or MRI.
7. Evidence of any other medical conditions (such as psychiatric illness, infectious diseases, neurological conditions, physical examination or laboratory findings) that may interfere with the planned treatment, affect patient compliance or place the patient at high risk from treatment related complications.
8. Breast feeding.
9. Concurrent malignancy requiring therapy (excluding non-invasive carcinoma or carcinoma in situ).
10. Patients requiring or undergoing concurrent treatment with live vaccines.
11. Patients requiring or undergoing concurrent treatment with phenytoin.
12. Known HIV positive status, active hepatitis B or C status.
13. Is taking any concurrent (or within 4 week prior to registration) anti-cancer therapy, immunotherapy, radiotherapy or any ancillary anti-cancer therapy; or any therapy that is considered to be investigational (i.e., used for non-approved indications(s) and in the context of a research investigation). Supportive care measures are allowed.
14. Patients unable to be regularly followed for any reason (geographic, familiar, social, psychological, housed in an institution e.g., prison because of a court agreement or administrative order). Patients who are dependent on the sponsor/CRO or investigational site as well as on the Investigator.
15. Use of concomitant treatment with QT/QTc prolonging drugs.
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 | EUCTR2013-001472-38-NL |
| ClinicalTrials.gov | NCT02098343 |
| CCMO | NL53070.068.15 |