Platinum Sensitive Recurrent High-grade Serous Ovarian Cancer With Mutated p53
Conditions
Keywords
Ovarian cancer, Ovarian carcinoma, High Grade Serous Ovarian Cancer, Recurrent Cancer, Resistant Cancer
Brief summary
The purpose of this study is to make a preliminary assessment of the efficacy of a combined APR-246 and carboplatin/PLD chemotherapy regimen, compared with carboplatin/PLD chemotherapy regimen alone, in patients with platinum sensitive recurrent high grade serous ovarian cancer (HGSOC) with mutated p53. In addition, the study aims 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, and to assess the biological activity in tumor and surrogate tissues. The trial will enroll up to a maximum of 400 patients.
Interventions
DRUGAPR-246
Intravenous infusion.
DRUGCarboplatin and Pegylated Liposomal Doxorubicin Hydrochloride (PLD)
Intravenous infusion.
Sponsors
Aprea Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed High Grade Serous Ovarian Cancer, and positive nuclear immunohistochemical (IHC) staining for p53 * Disease Progression between 6-24 months after a first or second platinum based regimen * At least a single measurable lesion. Phase II patients only * Adequate organ function prior to registration * Toxicities from previous cancer therapies must have recovered to grade 1 (defined by Common Terminology Criteria for Adverse Events \[CTCAE\] 4.0) Chronic stable grade 2 peripheral neuropathy secondary to neurotoxicity from prior therapies may be considered on a case by case basis * ECOG performance status of 0 to 1
Exclusion criteria
* Prior exposure to cumulative doses of doxorubicin \>400 mg/m2 or epirubicin \>720 mg/m2 * History of allergic reactions to carboplatin, platinum containing compounds or mannitol and/or hypersensitivity to PLD or to any of the excipients * Unable to undergo imaging by either CT scan or MRI * 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 * Concurrent malignancy requiring therapy (excluding non-invasive carcinoma or carcinoma in situ) * Is taking concurrent (or within 4 week prior to registration) chemotherapy, immunotherapy, radiotherapy, or any ancillary 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase Ib: Dose-limiting Toxicities (DLT) (See Description) of Combined APR-246 and Carboplatin/PLD Regimen | Until the end of the first treatment cycle, i.e., Day 28 | DLT: Hematological and non-hematological toxicities according to grade/days stated in the protocol. |
| Phase Ib and II: Progression Free Survival (PFS) | Up to 24 months | Phase Ib: Progression-free Survival is calculated from date of enrollment to the date of disease progression or death due to any cause, whichever occurs first. Symptomatic deterioration is not considered PD. For a patient without evidence of disease progression or death, Progression-free survival will be censored at the date of last evaluable tumor assessment. Patients with no evaluable tumor assessments will be censored at the date of first study drug administration. Phase II: Progression-free survival (PFS) based on Blinded Independent Central Review (BICR) is the primary endpoint and is defined as the number of days from the date of randomization to the date of objective disease progression or relapse (according to RECIST v1.1 only) or death due to any cause, whichever occurs first. If neither event occurs, PFS is censored at the date of the last evaluable tumor assessment. Symptomatic deterioration is not considered objective disease progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase Ib and Phase II: Overall Response Rate (RR) | Up to 24 months | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
Countries
Belgium, France, Germany, Netherlands, Spain, Sweden, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase Ib. APR-246 (35mg/kg) + Carboplatin/PLD. Dose escalation of APR-246.
APR-246: Intravenous infusion.
Carboplatin and Pegylated Liposomal Doxorubicin Hydrochloride (PLD): Intravenous infusion. | 9 |
| Phase Ib. APR-246 (50mg/kg) + Carboplatin/PLD. Dose escalation of APR-246.
APR-246: Intravenous infusion.
Carboplatin and Pegylated Liposomal Doxorubicin Hydrochloride (PLD): Intravenous infusion. | 6 |
| Phase Ib. APR-246 (67.5mg/kg) + Carboplatin/PLD. Dose escalation of APR-246.
APR-246: Intravenous infusion.
Carboplatin and Pegylated Liposomal Doxorubicin Hydrochloride (PLD): Intravenous infusion. | 20 |
| Phase II: Arm A. APR-246 + Carboplatin/PLD. Experimental
APR-246: Intravenous infusion.
Carboplatin and Pegylated Liposomal Doxorubicin Hydrochloride (PLD): Intravenous infusion. | 105 |
| Phase II: Arm B. Carboplatin/PLD. Active Comparator
Carboplatin and Pegylated Liposomal Doxorubicin Hydrochloride (PLD): Intravenous infusion. | 106 |
| Total | 246 |
Baseline characteristics
| Characteristic | Phase Ib. APR-246 (35mg/kg) + Carboplatin/PLD. | Phase Ib. APR-246 (50mg/kg) + Carboplatin/PLD. | Phase Ib. APR-246 (67.5mg/kg) + Carboplatin/PLD. | Phase II: Arm A. APR-246 + Carboplatin/PLD. | Phase II: Arm B. Carboplatin/PLD. | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 2 Participants | 10 Participants | 36 Participants | 49 Participants | 101 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 4 Participants | 10 Participants | 69 Participants | 57 Participants | 145 Participants |
| Age, Continuous | 63 years | 62 years | 64.5 years | 61 years | 64 years | 62 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 3 Participants | 3 Participants | 2 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 13 Participants | 22 Participants | 35 Participants |
| Race (NIH/OMB) White | 9 Participants | 6 Participants | 17 Participants | 88 Participants | 81 Participants | 201 Participants |
| Region of Enrollment Belgium | 2 participants | 1 participants | 4 participants | 10 participants | 10 participants | 27 participants |
| Region of Enrollment France | 0 participants | 0 participants | 0 participants | 12 participants | 20 participants | 32 participants |
| Region of Enrollment Germany | 0 participants | 0 participants | 0 participants | 1 participants | 10 participants | 11 participants |
| Region of Enrollment Netherlands | 0 participants | 0 participants | 0 participants | 12 participants | 2 participants | 14 participants |
| Region of Enrollment Spain | 0 participants | 0 participants | 0 participants | 19 participants | 22 participants | 41 participants |
| Region of Enrollment Sweden | 0 participants | 0 participants | 0 participants | 1 participants | 3 participants | 4 participants |
| Region of Enrollment United Kingdom | 7 participants | 5 participants | 16 participants | 33 participants | 19 participants | 80 participants |
| Region of Enrollment United States | 0 participants | 0 participants | 0 participants | 17 participants | 20 participants | 37 participants |
| Sex: Female, Male Female | 9 Participants | 6 Participants | 20 Participants | 105 Participants | 106 Participants | 246 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 9 | 3 / 6 | 10 / 20 | 0 / 99 | 2 / 101 |
| other Total, other adverse events | 9 / 9 | 6 / 6 | 20 / 20 | 99 / 99 | 101 / 101 |
| serious Total, serious adverse events | 3 / 9 | 4 / 6 | 12 / 20 | 31 / 99 | 17 / 101 |
Outcome results
Primary
Phase Ib and II: Progression Free Survival (PFS)
Phase Ib: Progression-free Survival is calculated from date of enrollment to the date of disease progression or death due to any cause, whichever occurs first. Symptomatic deterioration is not considered PD. For a patient without evidence of disease progression or death, Progression-free survival will be censored at the date of last evaluable tumor assessment. Patients with no evaluable tumor assessments will be censored at the date of first study drug administration. Phase II: Progression-free survival (PFS) based on Blinded Independent Central Review (BICR) is the primary endpoint and is defined as the number of days from the date of randomization to the date of objective disease progression or relapse (according to RECIST v1.1 only) or death due to any cause, whichever occurs first. If neither event occurs, PFS is censored at the date of the last evaluable tumor assessment. Symptomatic deterioration is not considered objective disease progression.
Time frame: Up to 24 months
Population: Ph Ib = Efficacy Evaluable~Ph II = ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase Ib. APR-246 (35mg/kg) + Carboplatin/PLD. | Phase Ib and II: Progression Free Survival (PFS) | 330 days |
| Phase Ib. APR-246 (50mg/kg) + Carboplatin/PLD. | Phase Ib and II: Progression Free Survival (PFS) | 277.5 days |
| Phase Ib. APR-246 (67.5mg/kg) + Carboplatin/PLD. | Phase Ib and II: Progression Free Survival (PFS) | 313 days |
| Phase II: Arm A. APR-246 + Carboplatin/PLD. | Phase Ib and II: Progression Free Survival (PFS) | 283 days |
| Phase II: Arm B. Carboplatin/PLD. | Phase Ib and II: Progression Free Survival (PFS) | 295 days |
Primary
Phase Ib: Dose-limiting Toxicities (DLT) (See Description) of Combined APR-246 and Carboplatin/PLD Regimen
DLT: Hematological and non-hematological toxicities according to grade/days stated in the protocol.
Time frame: Until the end of the first treatment cycle, i.e., Day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase Ib. APR-246 (35mg/kg) + Carboplatin/PLD. | Phase Ib: Dose-limiting Toxicities (DLT) (See Description) of Combined APR-246 and Carboplatin/PLD Regimen | 0 Participants |
| Phase Ib. APR-246 (50mg/kg) + Carboplatin/PLD. | Phase Ib: Dose-limiting Toxicities (DLT) (See Description) of Combined APR-246 and Carboplatin/PLD Regimen | 1 Participants |
| Phase Ib. APR-246 (67.5mg/kg) + Carboplatin/PLD. | Phase Ib: Dose-limiting Toxicities (DLT) (See Description) of Combined APR-246 and Carboplatin/PLD Regimen | 0 Participants |
Secondary
Phase Ib and Phase II: Overall Response Rate (RR)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: Up to 24 months
Population: Phase Ib = Efficacy Evaluable population~Phase II = ITT population
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase Ib. APR-246 (35mg/kg) + Carboplatin/PLD. | Phase Ib and Phase II: Overall Response Rate (RR) | Complete Response (CR) | 1 Participants |
| Phase Ib. APR-246 (35mg/kg) + Carboplatin/PLD. | Phase Ib and Phase II: Overall Response Rate (RR) | Partial response (PR) | 5 Participants |
| Phase Ib. APR-246 (35mg/kg) + Carboplatin/PLD. | Phase Ib and Phase II: Overall Response Rate (RR) | Progressive Disease (PD) | 0 Participants |
| Phase Ib. APR-246 (35mg/kg) + Carboplatin/PLD. | Phase Ib and Phase II: Overall Response Rate (RR) | Stable Disease (SD) | 1 Participants |
| Phase Ib. APR-246 (35mg/kg) + Carboplatin/PLD. | Phase Ib and Phase II: Overall Response Rate (RR) | Not Evaluable (NE) | 0 Participants |
| Phase Ib. APR-246 (50mg/kg) + Carboplatin/PLD. | Phase Ib and Phase II: Overall Response Rate (RR) | Complete Response (CR) | 0 Participants |
| Phase Ib. APR-246 (50mg/kg) + Carboplatin/PLD. | Phase Ib and Phase II: Overall Response Rate (RR) | Not Evaluable (NE) | 0 Participants |
| Phase Ib. APR-246 (50mg/kg) + Carboplatin/PLD. | Phase Ib and Phase II: Overall Response Rate (RR) | Partial response (PR) | 1 Participants |
| Phase Ib. APR-246 (50mg/kg) + Carboplatin/PLD. | Phase Ib and Phase II: Overall Response Rate (RR) | Stable Disease (SD) | 3 Participants |
| Phase Ib. APR-246 (50mg/kg) + Carboplatin/PLD. | Phase Ib and Phase II: Overall Response Rate (RR) | Progressive Disease (PD) | 0 Participants |
| Phase Ib. APR-246 (67.5mg/kg) + Carboplatin/PLD. | Phase Ib and Phase II: Overall Response Rate (RR) | Not Evaluable (NE) | 3 Participants |
| Phase Ib. APR-246 (67.5mg/kg) + Carboplatin/PLD. | Phase Ib and Phase II: Overall Response Rate (RR) | Complete Response (CR) | 2 Participants |
| Phase Ib. APR-246 (67.5mg/kg) + Carboplatin/PLD. | Phase Ib and Phase II: Overall Response Rate (RR) | Progressive Disease (PD) | 0 Participants |
| Phase Ib. APR-246 (67.5mg/kg) + Carboplatin/PLD. | Phase Ib and Phase II: Overall Response Rate (RR) | Partial response (PR) | 9 Participants |
| Phase Ib. APR-246 (67.5mg/kg) + Carboplatin/PLD. | Phase Ib and Phase II: Overall Response Rate (RR) | Stable Disease (SD) | 5 Participants |
| Phase II: Arm A. APR-246 + Carboplatin/PLD. | Phase Ib and Phase II: Overall Response Rate (RR) | Partial response (PR) | 42 Participants |
| Phase II: Arm A. APR-246 + Carboplatin/PLD. | Phase Ib and Phase II: Overall Response Rate (RR) | Not Evaluable (NE) | 11 Participants |
| Phase II: Arm A. APR-246 + Carboplatin/PLD. | Phase Ib and Phase II: Overall Response Rate (RR) | Progressive Disease (PD) | 15 Participants |
| Phase II: Arm A. APR-246 + Carboplatin/PLD. | Phase Ib and Phase II: Overall Response Rate (RR) | Stable Disease (SD) | 27 Participants |
| Phase II: Arm A. APR-246 + Carboplatin/PLD. | Phase Ib and Phase II: Overall Response Rate (RR) | Complete Response (CR) | 10 Participants |
| Phase II: Arm B. Carboplatin/PLD. | Phase Ib and Phase II: Overall Response Rate (RR) | Not Evaluable (NE) | 11 Participants |
| Phase II: Arm B. Carboplatin/PLD. | Phase Ib and Phase II: Overall Response Rate (RR) | Complete Response (CR) | 3 Participants |
| Phase II: Arm B. Carboplatin/PLD. | Phase Ib and Phase II: Overall Response Rate (RR) | Partial response (PR) | 50 Participants |
| Phase II: Arm B. Carboplatin/PLD. | Phase Ib and Phase II: Overall Response Rate (RR) | Progressive Disease (PD) | 5 Participants |
| Phase II: Arm B. Carboplatin/PLD. | Phase Ib and Phase II: Overall Response Rate (RR) | Stable Disease (SD) | 37 Participants |