Phase Ib/II Study of Carboplatin + M6620 + Avelumab in PARPi-resistant Ovarian Cancer

DLT: any death not clearly due to underlying disease/extraneous causes/Grade(Gr) >=3 nonhematologic/Gr>=4 hematologic toxicity that was probably/definitely related to any of study interventions, individually/combination that occurred during DLT observation period, except for any of following: Gr3 infusion-related reaction; Transient (<=6hr) Gr3 flu-like symptoms/fever, controlled with medical management; Transient (<=72hr) Gr3 fatigue, local reactions, headache, nausea/emesis; Gr3 diarrhea, skin toxicity, liver function test increase; Single laboratory values out of normal range and controlled with medical management; Tumor flare phenomenon: local pain, irritation/rash, localized at sites of known/suspected tumor; Neutropenia (Gr3/4) for <7 days not associated with any infection; Gr3 thrombocytopenia for <7 days without clinically significant bleeding and not requiring platelet transfusion; Symptomatic thyroid dysfunction manageable with treatment.

An adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs were defined as events that started or worsened after first dose of study intervention until 30 days after last dose. TEAEs included both serious and non-serious AEs. Treatment-related TEAE: reasonably related to the study intervention. The AE could medically (pharmacologically/clinically) be attributed to the study intervention under study in this clinical study protocol.

Confirmed BOR according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as assessed by an Investigator was defined as best response of any of the complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from the date of randomization until disease progression/ recurrence (taking the smallest measurement recorded since the start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. SD: Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. Number of participants with BOR in each category (CR, PR, SD, PD) were reported.

PFS according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as assessed by an Investigator was defined as the time from date of randomization until date of the first observation of progressive disease (PD) or death due to any cause within 12 weeks of the last tumor assessment in the absence of documented PD, whichever occurs first. PD was defined as at least a 20% increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. Participant wise data reported for this outcome measure.

DoR according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as assessed by an Investigator was defined as the time from first documentation of objective response (Complete Response [CR] or Partial Response [PR]) to the date of first documentation of objective progression of disease (PD) or death due to any cause whichever occurs first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. If a participant has not an event (PD or death), DoR was censored at the date of last adequate tumor assessment.

TTP according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and assessed by an Investigator was defined as the time from first dose of study intervention until progression disease (PD). PD was defined as at least a 20% increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. Participant wise data reported for this outcome measure.

The TFST was defined as the time from the date of randomization to the start date of the first subsequent anti-cancer therapy or death.

Area under the plasma concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule.

AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.

AUCtau was defined as area under the plasma concentration-time curve from time zero to the end of the dosing interval (tau). AUCtau was calculated using the mixed log linear trapezoidal rule.

Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.

Cmax was obtained directly from the concentration versus time curve.

Cmin was minimum observed plasma concentration obtained directly from the concentration versus time curve.

Tmax was obtained directly from the concentration versus time curve.

t1/2 was the time measured for the concentration to decrease by one half. t1/2 was calculated by natural log 2 divided by Lambda z.