Breast, Gastric Cancers, Ovarian, SCLC
Conditions
Keywords
MEDIOLA, Olaparib, MEDI4736, Bevacizumab, Ovarian cancer, Breast cancer, Small Cell Lung Cancer, Gastric Cancer, Phase I/II, Adults, PDL-1
Brief summary
The purpose of this study is to look at the effectiveness, safety, and antitumor activity of study drugs MEDI4736 in combination with olaparib (modules 1, 2, 3, 4, 5 and 7) and MEDI4736 in combination with olaparib and bevacizumab (module 6). It will also examine what happens to the study drugs in the body and investigate how well the combination between MEDI4736, olaparib and bevacizumab is tolerated.
Detailed description
This is a phase I/II open-label, multicenter study to evaluate the safety, tolerability, pharmacokinetics (PK) and antitumor activity of MEDI4736 in combination with olaparib in patients with advanced solid tumors, selected based on a rationale for response to olaparib. Patients will be poly (adenosine diphosphate-ribose) polymerase (PARP)-inhibitor and immunotherapy (IMT)-naïve (defined as no prior exposure to PARP inhibitors or IMT, including, but not limited to, other anti-cytotoxic T-lymphocyte-associated protein 4 \[CTLA-4\], anti-programmed cell death 1 \[PD-1\], anti-programmed death-ligand 1 \[PD-L1\] monoclonal antibodies, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). The 4 initial stage cohorts (Modules 1 to 4) include patients with relapsed small cell lung cancer (SCLC), germline BRCA mutated (gBRCAm) metastatic human epidermal growth factor receptor 2 (HER2)-negative breast cancer, gBRCAm platinum-sensitive relapsed ovarian cancer, and gastric cancer. The data cut-off occurred once all 4 Modules had reached last patient first visit (LPFV) + 2 years and all 4 cohorts had observed a median value for PFS. Second stage cohorts (Modules 5 to 7) include patients with relapsed gBRCAm platinum-sensitive relapsed ovarian cancer and non gBRCAm platinum-sensitive relapsed ovarian cancer. The final data cut-off will be once Modules 6 and 7 have observed a median value for overall survival. At this timepoint, the clinical study database will close to new data.
Interventions
DRUGOlaparib
Olaparib
DRUGMEDI4736
MEDI4736
DRUGBevacizumab
Bevacizumab
Sponsors
AstraZeneca
IQVIA Pty Ltd
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
* Patients must have histologically or cytologically confirmed progressive advanced or metastatic solid tumor of one of the following: * Platinum sensitive relapsed small cell lung cancer (module 1) * gBRCAm HER2-negative metastatic breast cancer (module 2) * gBRCAm ovarian cancer (modules 3 and 5) * Metastatic or relapsed Gastric cancer (adenocarcinoma) (module 4) * gBRCAm negative ovarian cancer (modules 6 and 7) * At least one measurable lesion that can be accurately assessed at baseline by computed tomography (CT) (or magnetic resonance imaging \[MRI\] suitable for assessment as per RECIST 1.1. The baseline scan must be obtained within 28 days prior to the first dose of olaparib. * Male or female patients, age ≥18 years (≥19 years for South Korea) * Eastern Cooperative Oncology Group (ECOG) performance status 0-1 * Life expectancy ≥12 weeks * Adequate organ and marrow function * Ability to swallow oral medications (capsules and tablets) without chewing, breaking, crushing, opening or otherwise altering the product formulation. Patients should not have gastrointestinal illnesses that would preclude the absorption of olaparib, which is an oral agent. For the gastric cancer cohort, patients with a full or partial gastrectomy will be permitted. * Ability of patient to understand and the willingness to sign a written informed consent document prior to any protocol related procedures, including screening evaluations. * Female patients must either: * Be of non-reproductive potential OR * Have a negative serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on Day 1, and agree to use contraception if they or their partner are of reproductive potential
Exclusion criteria
* Prior chemotherapy or other systemic anticancer therapy within 4 weeks prior to start of olaparib treatment, 6 weeks for nitrosoureas or mitomycin. Exceptions include: Anti-hormonal treatment for ER positive or PR positive breast cancer is allowed until 7 days prior to treatment with olaparib, exposure to an investigational agent within 30 days or 5 half-lives (whichever is the longer) prior to start of olaparib treatment is not allowed, prior receipt of biologics targeting T cell co-regulatory proteins and/or immune checkpoints is not allowed. Examples include MEDI4736 or other PD1 or PD-L1 or PD-L2 inhibitors or anti-CTLA4 therapy, previous treatment with a PARP inhibitor, is not allowed. * Radiation therapy within 4 weeks prior to start of olaparib treatment (includes radiation targeting bone metastases) or radionuclide treatment within 6 weeks of treatment start. * Current dependency on total parenteral nutrition or IV fluid hydration. * Concomitant use of known strong cytochrome P450 (CYP) 3A (CYP3A) inhibitors or moderate CYP3A inhibitors. Concomitant use of known strong or moderate CYP3A inducers. * Concomitant therapy with any other anticancer therapy or chronic use of systemic corticosteroids. * Previous allogenic bone marrow transplant or double umbilical cord blood transplantation * Whole blood transfusions in the last 120 days * Patients with symptomatic or uncontrolled brain metastases. * Patients being considered at poor medical risk due to a serious, uncontrolled medical disorder or non-malignant systemic disease. * Any psychiatric disorder that prohibits obtaining informed consent * Major surgery or significant traumatic injury within 2 weeks of run-in * Immunocompromised patients * QTc prolongation \>470 msec or other significant ECG abnormality noted within 14 days of treatment * Pregnant and breastfeeding women are excluded. * Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site) * Previous enrolment in the present study * Participation in a clinical study within 28 days or 5 half-lives of the drug, whichever is longer.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Initial Stage Cohorts: Disease Control Rate (DCR) at Week 12 | RECIST performed at baseline, at 4 weeks after first dose of olaparib monotherapy and every 8 weeks +/-7 days thereafter. Assessed until DCO 14 Jun 2019. | The DCR at 12 weeks was defined as the percentage of participants who had complete response (CR) + partial response (PR) + stable disease (SD) at 12 weeks. Participants demonstrated SD for a minimum interval of 11 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e. 77 days) following the start of treatment. The DCR was determined using Investigator assessments according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). |
| Second Stage Cohort: Objective Response Rate (ORR) | RECIST performed at baseline, and every 8 weeks +/-7 days thereafter. Assessed until 17 Sep 2021. | The ORR (based on RECIST 1.1 as assessed by the Investigator) was defined as the percentage of participants with at least 1 visit response of CR or PR prior to PD or last evaluable assessment in the absence of progression. The 95% confidence interval (CI) were calculated using Exact Clopper-Pearson confidence limits for the binomial proportion. |
| Second Stage Cohorts: DCR at Week 24 | RECIST performed at baseline, and every 8 weeks +/-7 days thereafter. Assessed until 17 Sep 2021. | The DCR at 24 weeks was defined as the percentage of participants who had CR + PR + SD at 24 weeks. Participants demonstrated SD for a minimum interval of 23 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e. 161 days) following the start of treatment. The DCR was determined using Investigator assessments according to RECIST v1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Second Stage Expansion Cohort: DCR at Week 24 | RECIST performed at baseline, and every 8 weeks +/-7 days thereafter. Assessed until 17 Sep 2021. | The DCR at 24 weeks was defined as the percentage of participants who had CR + PR + SD at 24 weeks. Participants demonstrated SD for a minimum interval of 23 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e. 161 days) following the start of treatment. The DCR was determined using Investigator assessments according to RECIST v1.1. |
| Initial Stage Cohorts: DCR at Week 28 | RECIST performed at baseline, at 4 weeks after first dose of olaparib monotherapy and every 8 weeks +/-7 days thereafter. Assessed until DCO 14 Jun 2019. | The DCR at 28 weeks was defined as the percentage of participants who had CR + PR + SD at 28 weeks. Participants demonstrated SD for a minimum interval of 27 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e. 189 days) following the start of treatment. The DCR was determined using Investigator assessments according to RECIST v1.1. |
| Second Stage Cohorts: DCR at Week 56 | RECIST performed at baseline, and every 8 weeks +/-7 days thereafter. Assessed until 17 Sep 2021. | The DCR at 56 weeks was defined as the percentage of participants who had CR + PR + SD at 56 weeks. Participants demonstrated SD for a minimum interval of 55 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e. 385 days) following the start of treatment. The DCR was determined using Investigator assessments according to RECIST v1.1. |
| Initial and Second Stage Cohorts: ORR | RECIST performed at baseline, at 4 weeks after first dose of olaparib monotherapy (for initial stage cohort only) and every 8 weeks +/-7 days thereafter. Assessed until DCO 14 Jun 2019 and 17 Sep 2021 for initial and second stage cohorts, respectively | The ORR (based on RECIST 1.1 as assessed by the Investigator) was defined as the percentage of participants with at least 1 visit response of CR or PR prior to PD or last evaluable assessment in the absence of progression. The 95% CI were calculated using Exact Clopper-Pearson confidence limits for the binomial proportion. |
| Initial and Second Stage Cohorts: Duration of Response (DoR) | RECIST performed at baseline, at 4 weeks after first dose of olaparib monotherapy (for initial stage cohort only) and every 8 weeks +/-7 days thereafter. Assessed until DCO 14 Jun 2019 and 17 Sep 2021 for initial and second stage cohorts, respectively | The DoR (based on RECIST 1.1 as assessed by the Investigator) was defined as the time from the date of first documented response until date of documented progression or death in the absence of PD. The DoR was calculated using Kaplan-Meier technique. |
| Initial and Second Stage Cohorts: Progression-Free Survival (PFS) | RECIST performed at baseline, at 4 weeks after first dose of olaparib monotherapy (for initial stage cohort only) and every 8 weeks +/-7 days thereafter. Assessed until DCO 14 Jun 2019 and 17 Sep 2021 for initial and second stage cohorts, respectively | The PFS (based on RECIST 1.1 as assessed by the Investigator) was defined as the time from start of study treatment (Day 1; start of olaparib monotherapy for initial stage cohorts) until the date of objective PD or death (by any cause in the absence of disease progression) regardless of whether the patient withdraws from therapy or receives another anticancer therapy prior to disease progression. The PFS was calculated using Kaplan-Meier technique. |
| Initial Stage Cohorts: Percentage Change From Baseline in Target Tumor Size at Weeks 12 and 28 | Baseline (Day 1) and Weeks 12 and 28. Assessed until DCO 14 Jun 2019 | The percentage change in target tumor size at each timepoint (based on RECIST 1.1 target lesion measurements) was obtained for each participant taking the difference between the sum of the target lesions at each timepoint and the sum of the target lesions at baseline divided by the sum of the target lesions at baseline times 100. Baseline was defined as the last evaluable assessment prior to starting olaparib treatment. |
| Second Stage Cohorts: Percentage Change From Baseline in Target Tumor Size at Weeks 24 and 56 | Baseline (Day 1) and Weeks 24 and 56. Assessed until DCO 17 Sep 2021 | The percentage change in target tumor size at each timepoint (based on RECIST 1.1 target lesion measurements) was obtained for each participant taking the difference between the sum of the target lesions at each timepoint and the sum of the target lesions at baseline divided by the sum of the target lesions at baseline times 100. Baseline was defined as the last assessment prior to Cycle 1 Day 1. |
| Initial and Second Stage Cohorts: Best Percentage Change From Baseline in Target Tumor Size | From baseline (Day 1) until confirmed PD/death. Assessed until DCO 14 Jun 2019 and 17 Sep 2021 for initial and second stage cohorts, respectively | The best percentage change from baseline in target tumor size was based on RECIST 1.1 target lesion measurements taken at each RECIST 1.1 assessment. All measurements until PD or the last evaluable assessment in the absence of PD was included in the calculation. Baseline was defined as the last evaluable assessment prior to starting olaparib treatment for initial stage cohorts. Baseline was defined as the last assessment prior to Cycle 1 Day 1 for second stage cohorts. |
| Initial and Second Stage Cohorts: Time to Study Treatment Discontinuation or Death (TDT) | From baseline (Day 1) until treatment discontinuation/death. Assessed until DCO 14 Jun 2019 and 17 Sep 2021 for initial and second stage cohorts, respectively | The TDT was defined as the time from start of study treatment (Day 1; start of olaparib monotherapy for initial stage cohorts) to the earlier of the date of study treatment discontinuation or death. The TDT was calculated using the Kaplan-Meier technique. |
| Initial and Second Stage Cohorts: OS | From baseline (Day 1) until death from any cause. Assessed until DCO 14 Jun 2019 for initial stage cohorts except for ovarian cancer cohort and DCO 17 Sep 2021 for initial stage ovarian cancer cohort and second stage cohorts | The OS was defined as the time from the start of study treatment (Day 1; start of olaparib monotherapy for initial stage cohorts) until death due to any cause. The OS was calculated using the Kaplan-Meier technique. |
| Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Pre-dose and within 10 minutes of end of infusion on Days 1, 85 and 113; Pre-dose on Days 29, 57 and 169; and 90 days post last dose of MEDI4736. Assessed until DCO 14 Jun 2019 and 17 Sep 2021 for initial and second stage cohorts, respectively | Blood samples were collected to determine the serum concentration of MEDI4736. |
| Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Pre-dose and 0.5-1 hour postdose on Days 1 and 22 of monotherapy; Pre-dose and 0.5-1, 1-3, 3-6 and 6-12 hours postdose on Day 15 of combination therapy. Assessed until DCO 14 Jun 2019 and 17 Sep 2021 for initial and second stage cohorts, respectively | Blood samples were collected to determine the serum concentration of olaparib. |
| Second Stage Cohort: Serum Concentrations of Bevacizumab | Pre-dose and within 10 minutes of end of infusion on Days 1 and 85; Pre-dose on Days 29 and 169; and 90 days post last dose of bevacizumab. Assessed until DCO 17 Sep 2021 | Blood samples were collected to determine the serum concentration of bevacizumab. |
| Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | Pre-dose on Days 1, 15, 57, 85, 113 and 169; and 90 days post-last dose of MEDI4736. Assessed until DCO 14 Jun 2019 and 17 Sep 2021 for initial and second stage cohorts, respectively | Blood samples were measured for the presence of ADAs and ADA-neutralizing antibodies (nAb) for MEDI4736 using validated assays. ADA prevalence was defined as the percentage of participants with positive ADA result at any time, baseline or post-baseline. ADA incidence (treatment-emergent ADA) was defined as the sum of both treatment-induced (post-baseline ADA positive only) and treatment-boosted ADA. Treatment-boosted ADA was defined as baseline ADA titer that was boosted to 4-fold or higher following drug administration. Persistently positive was defined as positive at \>=2 post-baseline assessments (with \>=16 weeks between first and last positive) or positive at last post-baseline assessment. Transiently positive was defined as having at least 1 post-baseline ADA positive assessment and not fulfilling the conditions of persistently positive. |
Countries
France, Israel, Netherlands, South Korea, Switzerland, United Kingdom, United States
Contacts
PRINCIPAL_INVESTIGATORSusan Domchek, MD
Abramson Cancer Center, University of Pennsylvania
Participant flow
Recruitment details
This Phase I/II open-label study was conducted in participants with advanced solid tumors at 43 centers in France, the United Kingdom, the Republic of Korea, the USA, the Netherlands, Israel, and Switzerland. Initial stage cohorts: Results are reported for analysis with assessment until data cut-off (DCO) of 14 Jun 2019 \[except for overall survival (OS) for ovarian cancer cohort (DCO: 17 Sep 2021)\]. Second stage cohorts: Results are reported for analysis with assessment until DCO of 17 Sep 2021.
Pre-assignment details
This study consists a screening period (28 days), run-in monotherapy treatment period (initial stage cohort only; 4 weeks) followed by combination therapy treatment period until progressive disease (PD). 148 participants entered initial stage cohorts and 114 participants entered second stage cohorts. Thus, 262 participants were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| Initial Stage: Small Cell Lung Cancer Participants received monotherapy with olaparib 300 mg orally twice daily for 4 weeks. Participants then continued to receive combination therapy with olaparib and MEDI4736 1.5 g IV infusion every 4 weeks in 28-day cycle until PD or specific treatment discontinuation criteria were met. | 38 |
| Initial Stage: Breast Cancer Participants received monotherapy with olaparib 300 mg orally twice daily for 4 weeks. Participants then continued to receive combination therapy with olaparib and MEDI4736 1.5 g IV infusion every 4 weeks in 28-day cycle until PD or specific treatment discontinuation criteria were met. | 30 |
| Initial Stage: Ovarian Cancer Participants received monotherapy with olaparib 300 mg orally twice daily for 4 weeks. Participants then continued to receive combination therapy with olaparib and MEDI4736 1.5 g IV infusion every 4 weeks in 28-day cycle until PD or specific treatment discontinuation criteria were met. | 32 |
| Initial Stage: Gastric Cancer Participants received monotherapy with olaparib 300 mg orally twice daily for 4 weeks. Participants then continued to receive combination therapy with olaparib and MEDI4736 1.5 g IV infusion every 4 weeks in 28-day cycle until PD or specific treatment discontinuation criteria were met. | 39 |
| Second Stage: Ovarian Cancer Expansion Participants received combination therapy with olaparib 300 mg orally twice daily and MEDI4736 1.5 g IV infusion every 4 weeks in 28-day cycle until PD or specific treatment discontinuation criteria were met. | 51 |
| Second Stage: Ovarian Cancer Triplet Participants received combination therapy with olaparib 300 mg orally twice daily plus MEDI4736 1.5 g IV infusion every 4 weeks plus bevacizumab 10 mg/kg IV infusion every 2 weeks in 28-day cycle until PD or specific treatment discontinuation criteria were met. | 31 |
| Second Stage: Ovarian Cancer Doublet Participants received combination therapy with olaparib 300 mg orally twice daily and MEDI4736 1.5 g IV infusion every 4 weeks in 28-day cycle until PD or specific treatment discontinuation criteria were met. | 32 |
| Total | 253 |
Baseline characteristics
| Characteristic | Initial Stage: Small Cell Lung Cancer | Initial Stage: Breast Cancer | Initial Stage: Ovarian Cancer | Initial Stage: Gastric Cancer | Second Stage: Ovarian Cancer Expansion | Second Stage: Ovarian Cancer Triplet | Second Stage: Ovarian Cancer Doublet | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 15 Participants | 1 Participants | 5 Participants | 10 Participants | 13 Participants | 14 Participants | 20 Participants | 78 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants | 29 Participants | 27 Participants | 29 Participants | 38 Participants | 17 Participants | 12 Participants | 175 Participants |
| Race/Ethnicity, Customized Asian | 6 Participants | 7 Participants | 6 Participants | 13 Participants | 12 Participants | 10 Participants | 3 Participants | 57 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Missing | 11 Participants | 6 Participants | 4 Participants | 2 Participants | 4 Participants | 0 Participants | 5 Participants | 32 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 27 Participants | 24 Participants | 28 Participants | 37 Participants | 47 Participants | 30 Participants | 27 Participants | 220 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 21 Participants | 17 Participants | 22 Participants | 24 Participants | 34 Participants | 20 Participants | 24 Participants | 162 Participants |
| Sex: Female, Male Female | 17 Participants | 29 Participants | 32 Participants | 13 Participants | 51 Participants | 31 Participants | 32 Participants | 205 Participants |
| Sex: Female, Male Male | 21 Participants | 1 Participants | 0 Participants | 26 Participants | 0 Participants | 0 Participants | 0 Participants | 48 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 | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 36 / 40 | 24 / 34 | 26 / 34 | 35 / 40 | 13 / 51 | 17 / 31 | 20 / 32 |
| other Total, other adverse events | 40 / 40 | 34 / 34 | 32 / 34 | 40 / 40 | 50 / 51 | 31 / 31 | 32 / 32 |
| serious Total, serious adverse events | 23 / 40 | 4 / 34 | 10 / 34 | 10 / 40 | 13 / 51 | 6 / 31 | 8 / 32 |
Outcome results
Primary
Initial Stage Cohorts: Disease Control Rate (DCR) at Week 12
The DCR at 12 weeks was defined as the percentage of participants who had complete response (CR) + partial response (PR) + stable disease (SD) at 12 weeks. Participants demonstrated SD for a minimum interval of 11 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e. 77 days) following the start of treatment. The DCR was determined using Investigator assessments according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).
Time frame: RECIST performed at baseline, at 4 weeks after first dose of olaparib monotherapy and every 8 weeks +/-7 days thereafter. Assessed until DCO 14 Jun 2019.
Population: The full analysis set included all participants who received at least 1 dose of study treatment and had no important protocol deviation resulting in exclusion from the analysis set as defined in the Statistical Analysis Plan (i.e, not meeting key eligibility criteria).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Initial Stage: Small Cell Lung Cancer | Initial Stage Cohorts: Disease Control Rate (DCR) at Week 12 | 28.9 percentage of participants |
| Initial Stage: Breast Cancer | Initial Stage Cohorts: Disease Control Rate (DCR) at Week 12 | 80.0 percentage of participants |
| Initial Stage: Ovarian Cancer | Initial Stage Cohorts: Disease Control Rate (DCR) at Week 12 | 81.3 percentage of participants |
| Initial Stage: Gastric Cancer | Initial Stage Cohorts: Disease Control Rate (DCR) at Week 12 | 25.6 percentage of participants |
Primary
Second Stage Cohort: Objective Response Rate (ORR)
The ORR (based on RECIST 1.1 as assessed by the Investigator) was defined as the percentage of participants with at least 1 visit response of CR or PR prior to PD or last evaluable assessment in the absence of progression. The 95% confidence interval (CI) were calculated using Exact Clopper-Pearson confidence limits for the binomial proportion.
Time frame: RECIST performed at baseline, and every 8 weeks +/-7 days thereafter. Assessed until 17 Sep 2021.
Population: The full analysis set included all participants who received at least 1 dose of study treatment and had no important protocol deviation resulting in exclusion from the analysis set as defined in the Statistical Analysis Plan (i.e, not meeting key eligibility criteria).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Initial Stage: Small Cell Lung Cancer | Second Stage Cohort: Objective Response Rate (ORR) | 92.2 percentage of participants |
Primary
Second Stage Cohorts: DCR at Week 24
The DCR at 24 weeks was defined as the percentage of participants who had CR + PR + SD at 24 weeks. Participants demonstrated SD for a minimum interval of 23 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e. 161 days) following the start of treatment. The DCR was determined using Investigator assessments according to RECIST v1.1.
Time frame: RECIST performed at baseline, and every 8 weeks +/-7 days thereafter. Assessed until 17 Sep 2021.
Population: The full analysis set included all participants who received at least 1 dose of study treatment and had no important protocol deviation resulting in exclusion from the analysis set as defined in the Statistical Analysis Plan (i.e, not meeting key eligibility criteria).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Initial Stage: Small Cell Lung Cancer | Second Stage Cohorts: DCR at Week 24 | 74.2 percentage of participants |
| Initial Stage: Breast Cancer | Second Stage Cohorts: DCR at Week 24 | 28.1 percentage of participants |
Secondary
Initial and Second Stage Cohorts: Best Percentage Change From Baseline in Target Tumor Size
The best percentage change from baseline in target tumor size was based on RECIST 1.1 target lesion measurements taken at each RECIST 1.1 assessment. All measurements until PD or the last evaluable assessment in the absence of PD was included in the calculation. Baseline was defined as the last evaluable assessment prior to starting olaparib treatment for initial stage cohorts. Baseline was defined as the last assessment prior to Cycle 1 Day 1 for second stage cohorts.
Time frame: From baseline (Day 1) until confirmed PD/death. Assessed until DCO 14 Jun 2019 and 17 Sep 2021 for initial and second stage cohorts, respectively
Population: The full analysis set included all participants who received at least 1 dose of study treatment and had no important protocol deviation resulting in exclusion from the analysis set as defined in the Statistical Analysis Plan (i.e, not meeting key eligibility criteria). Only participants with at least 1 post baseline RECIST target lesion assessment scan were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Best Percentage Change From Baseline in Target Tumor Size | 6.27 percentage change in tumor size | Standard Deviation 32.398 |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Best Percentage Change From Baseline in Target Tumor Size | -47.60 percentage change in tumor size | Standard Deviation 36.823 |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Best Percentage Change From Baseline in Target Tumor Size | -55.55 percentage change in tumor size | Standard Deviation 35.789 |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Best Percentage Change From Baseline in Target Tumor Size | 1.64 percentage change in tumor size | Standard Deviation 42.338 |
| Second Stage: Ovarian Cancer Triplet | Initial and Second Stage Cohorts: Best Percentage Change From Baseline in Target Tumor Size | -72.78 percentage change in tumor size | Standard Deviation 31.497 |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Best Percentage Change From Baseline in Target Tumor Size | -53.30 percentage change in tumor size | Standard Deviation 33.317 |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Best Percentage Change From Baseline in Target Tumor Size | -20.42 percentage change in tumor size | Standard Deviation 41.16 |
Secondary
Initial and Second Stage Cohorts: Duration of Response (DoR)
The DoR (based on RECIST 1.1 as assessed by the Investigator) was defined as the time from the date of first documented response until date of documented progression or death in the absence of PD. The DoR was calculated using Kaplan-Meier technique.
Time frame: RECIST performed at baseline, at 4 weeks after first dose of olaparib monotherapy (for initial stage cohort only) and every 8 weeks +/-7 days thereafter. Assessed until DCO 14 Jun 2019 and 17 Sep 2021 for initial and second stage cohorts, respectively
Population: The full analysis set included all participants who received at least 1 dose of study treatment and had no important protocol deviation resulting in exclusion from the analysis set as defined in the Statistical Analysis Plan (i.e, not meeting key eligibility criteria). Only participants with objective response were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Duration of Response (DoR) | 3.6 months |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Duration of Response (DoR) | 9.2 months |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Duration of Response (DoR) | 10.2 months |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Duration of Response (DoR) | 14.8 months |
| Second Stage: Ovarian Cancer Triplet | Initial and Second Stage Cohorts: Duration of Response (DoR) | 14.8 months |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Duration of Response (DoR) | 11.1 months |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Duration of Response (DoR) | 6.9 months |
Secondary
Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736
Blood samples were measured for the presence of ADAs and ADA-neutralizing antibodies (nAb) for MEDI4736 using validated assays. ADA prevalence was defined as the percentage of participants with positive ADA result at any time, baseline or post-baseline. ADA incidence (treatment-emergent ADA) was defined as the sum of both treatment-induced (post-baseline ADA positive only) and treatment-boosted ADA. Treatment-boosted ADA was defined as baseline ADA titer that was boosted to 4-fold or higher following drug administration. Persistently positive was defined as positive at \>=2 post-baseline assessments (with \>=16 weeks between first and last positive) or positive at last post-baseline assessment. Transiently positive was defined as having at least 1 post-baseline ADA positive assessment and not fulfilling the conditions of persistently positive.
Time frame: Pre-dose on Days 1, 15, 57, 85, 113 and 169; and 90 days post-last dose of MEDI4736. Assessed until DCO 14 Jun 2019 and 17 Sep 2021 for initial and second stage cohorts, respectively
Population: The ADA analysis set included all participants in the safety analysis set who have non-missing baseline ADA and at least 1 non-missing post-baseline ADA result for MEDI4736.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | Any nAb positive among any ADA positive | 0 Participants |
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | Persistent positive | 0 Participants |
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA positive post-baseline and positive at baseline | 0 Participants |
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | Transient positive | 0 Participants |
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA incidence | 0 Participants |
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA not detected post-baseline and positive at baseline | 0 Participants |
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA positive post-baseline and not detected at baseline | 0 Participants |
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA prevalence | 0 Participants |
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | Treatment-boosted ADA | 0 Participants |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | Any nAb positive among any ADA positive | 0 Participants |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA positive post-baseline and positive at baseline | 0 Participants |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | Transient positive | 0 Participants |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | Treatment-boosted ADA | 0 Participants |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA positive post-baseline and not detected at baseline | 0 Participants |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | Persistent positive | 0 Participants |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA incidence | 0 Participants |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA prevalence | 1 Participants |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA not detected post-baseline and positive at baseline | 0 Participants |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA not detected post-baseline and positive at baseline | 0 Participants |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA positive post-baseline and positive at baseline | 0 Participants |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA positive post-baseline and not detected at baseline | 0 Participants |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | Treatment-boosted ADA | 0 Participants |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | Transient positive | 0 Participants |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | Any nAb positive among any ADA positive | 0 Participants |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA prevalence | 0 Participants |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA incidence | 0 Participants |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | Persistent positive | 0 Participants |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | Treatment-boosted ADA | 0 Participants |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | Transient positive | 0 Participants |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA positive post-baseline and positive at baseline | 0 Participants |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | Any nAb positive among any ADA positive | 0 Participants |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA not detected post-baseline and positive at baseline | 0 Participants |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA prevalence | 0 Participants |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA incidence | 0 Participants |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA positive post-baseline and not detected at baseline | 0 Participants |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | Persistent positive | 0 Participants |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | Any nAb positive among any ADA positive | 0 Participants |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | Treatment-boosted ADA | 0 Participants |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA prevalence | 0 Participants |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA positive post-baseline and not detected at baseline | 0 Participants |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA incidence | 0 Participants |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | Persistent positive | 0 Participants |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA positive post-baseline and positive at baseline | 0 Participants |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | Transient positive | 0 Participants |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA not detected post-baseline and positive at baseline | 0 Participants |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | Any nAb positive among any ADA positive | 0 Participants |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | Treatment-boosted ADA | 0 Participants |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA positive post-baseline and not detected at baseline | 0 Participants |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA incidence | 0 Participants |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA positive post-baseline and positive at baseline | 0 Participants |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | Persistent positive | 0 Participants |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA prevalence | 0 Participants |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | ADA not detected post-baseline and positive at baseline | 0 Participants |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | Transient positive | 0 Participants |
Secondary
Initial and Second Stage Cohorts: ORR
The ORR (based on RECIST 1.1 as assessed by the Investigator) was defined as the percentage of participants with at least 1 visit response of CR or PR prior to PD or last evaluable assessment in the absence of progression. The 95% CI were calculated using Exact Clopper-Pearson confidence limits for the binomial proportion.
Time frame: RECIST performed at baseline, at 4 weeks after first dose of olaparib monotherapy (for initial stage cohort only) and every 8 weeks +/-7 days thereafter. Assessed until DCO 14 Jun 2019 and 17 Sep 2021 for initial and second stage cohorts, respectively
Population: The full analysis set included all participants who received at least 1 dose of study treatment and had no important protocol deviation resulting in exclusion from the analysis set as defined in the Statistical Analysis Plan (i.e, not meeting key eligibility criteria).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: ORR | 10.5 percentage of participants |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: ORR | 63.3 percentage of participants |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: ORR | 71.9 percentage of participants |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: ORR | 10.3 percentage of participants |
| Second Stage: Ovarian Cancer Triplet | Initial and Second Stage Cohorts: ORR | 87.1 percentage of participants |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: ORR | 34.4 percentage of participants |
Secondary
Initial and Second Stage Cohorts: OS
The OS was defined as the time from the start of study treatment (Day 1; start of olaparib monotherapy for initial stage cohorts) until death due to any cause. The OS was calculated using the Kaplan-Meier technique.
Time frame: From baseline (Day 1) until death from any cause. Assessed until DCO 14 Jun 2019 for initial stage cohorts except for ovarian cancer cohort and DCO 17 Sep 2021 for initial stage ovarian cancer cohort and second stage cohorts
Population: The full analysis set included all participants who received at least 1 dose of study treatment and had no important protocol deviation resulting in exclusion from the analysis set as defined in the Statistical Analysis Plan (i.e, not meeting key eligibility criteria).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: OS | 7.6 months |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: OS | 20.5 months |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: OS | 35.5 months |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: OS | 6.4 months |
| Second Stage: Ovarian Cancer Triplet | Initial and Second Stage Cohorts: OS | NA months |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: OS | 31.9 months |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: OS | 26.1 months |
Secondary
Initial and Second Stage Cohorts: Progression-Free Survival (PFS)
The PFS (based on RECIST 1.1 as assessed by the Investigator) was defined as the time from start of study treatment (Day 1; start of olaparib monotherapy for initial stage cohorts) until the date of objective PD or death (by any cause in the absence of disease progression) regardless of whether the patient withdraws from therapy or receives another anticancer therapy prior to disease progression. The PFS was calculated using Kaplan-Meier technique.
Time frame: RECIST performed at baseline, at 4 weeks after first dose of olaparib monotherapy (for initial stage cohort only) and every 8 weeks +/-7 days thereafter. Assessed until DCO 14 Jun 2019 and 17 Sep 2021 for initial and second stage cohorts, respectively
Population: The full analysis set included all participants who received at least 1 dose of study treatment and had no important protocol deviation resulting in exclusion from the analysis set as defined in the Statistical Analysis Plan (i.e, not meeting key eligibility criteria).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Progression-Free Survival (PFS) | 2.4 months |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Progression-Free Survival (PFS) | 8.2 months |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Progression-Free Survival (PFS) | 12.0 months |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Progression-Free Survival (PFS) | 2.6 months |
| Second Stage: Ovarian Cancer Triplet | Initial and Second Stage Cohorts: Progression-Free Survival (PFS) | 15.0 months |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Progression-Free Survival (PFS) | 14.7 months |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Progression-Free Survival (PFS) | 5.5 months |
Secondary
Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736
Blood samples were collected to determine the serum concentration of MEDI4736.
Time frame: Pre-dose and within 10 minutes of end of infusion on Days 1, 85 and 113; Pre-dose on Days 29, 57 and 169; and 90 days post last dose of MEDI4736. Assessed until DCO 14 Jun 2019 and 17 Sep 2021 for initial and second stage cohorts, respectively
Population: The MEDI4736 pharmacokinetic (PK) analysis set included all participants who received at least 1 dose of MEDI4736 and provided evaluable MEDI4736 PK profile for at least 1 treatment period.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 1: Pre-dose | NA microgram per milliliter (mcg/mL) | — |
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 113: End of infusion | 504.8 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 25.24 |
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | 90 days post last dose | 6.907 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 297.9 |
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 169: Pre-dose | 133.1 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 30.74 |
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 57: Pre-dose | 144.7 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 38.96 |
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 1: End of infusion | 483.5 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 35.09 |
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 113: Pre-dose | 119.5 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 44.27 |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | 90 days post last dose | 12.24 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 4720 |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 1: Pre-dose | NA microgram per milliliter (mcg/mL) | — |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 169: Pre-dose | 231.5 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 41.14 |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 113: End of infusion | 671.5 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 31.79 |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 1: End of infusion | 542.5 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 36.04 |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 113: Pre-dose | 220.7 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 35.97 |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 57: Pre-dose | 165.2 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 40.31 |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 1: Pre-dose | NA microgram per milliliter (mcg/mL) | — |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | 90 days post last dose | 22.35 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 120.9 |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 57: Pre-dose | 171.3 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 31.73 |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 1: End of infusion | 417.9 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 33.48 |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 113: Pre-dose | 231.3 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 33.45 |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 113: End of infusion | 585.5 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 52.67 |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 169: Pre-dose | 261.6 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 45.92 |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 57: Pre-dose | 114.7 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 44.78 |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 1: Pre-dose | NA microgram per milliliter (mcg/mL) | — |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 169: Pre-dose | 230.7 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 35.81 |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 113: Pre-dose | 196.9 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 74.6 |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 113: End of infusion | 679.1 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 34.8 |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | 90 days post last dose | 17.23 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 155.2 |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 1: End of infusion | 391.8 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 25.09 |
| Second Stage: Ovarian Cancer Triplet | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 85: End of infusion | 610.6 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 39.64 |
| Second Stage: Ovarian Cancer Triplet | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | 90 days post last dose | 17.94 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 331.8 |
| Second Stage: Ovarian Cancer Triplet | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 85: Pre-dose | 152.8 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 50.14 |
| Second Stage: Ovarian Cancer Triplet | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 1: End of infusion | 409.3 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 33.27 |
| Second Stage: Ovarian Cancer Triplet | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 29: Pre-dose | 93.56 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 54.83 |
| Second Stage: Ovarian Cancer Triplet | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 1: Pre-dose | NA microgram per milliliter (mcg/mL) | — |
| Second Stage: Ovarian Cancer Triplet | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 169: Pre-dose | 206.3 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 61.24 |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 1: Pre-dose | NA microgram per milliliter (mcg/mL) | — |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 1: End of infusion | 498.8 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 30.27 |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 29: Pre-dose | 96.50 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 34.67 |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 85: Pre-dose | 145.2 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 55.71 |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 85: End of infusion | 589.3 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 35.48 |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 169: Pre-dose | 162.6 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 95.86 |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | 90 days post last dose | 17.47 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 78.93 |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | 90 days post last dose | 20.50 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 340 |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 169: Pre-dose | 186.6 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 65.36 |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 85: End of infusion | 482.9 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 44.01 |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 85: Pre-dose | 142.8 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 63.07 |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 29: Pre-dose | 78.23 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 56.6 |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 1: End of infusion | 397.1 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 18.53 |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Day 1: Pre-dose | NA microgram per milliliter (mcg/mL) | — |
Secondary
Initial and Second Stage Cohorts: Serum Concentrations of Olaparib
Blood samples were collected to determine the serum concentration of olaparib.
Time frame: Pre-dose and 0.5-1 hour postdose on Days 1 and 22 of monotherapy; Pre-dose and 0.5-1, 1-3, 3-6 and 6-12 hours postdose on Day 15 of combination therapy. Assessed until DCO 14 Jun 2019 and 17 Sep 2021 for initial and second stage cohorts, respectively
Population: The olaparib PK analysis set included all participants who received at least 1 dose of olaparib and provided evaluable olaparib PK profile for at least 1 treatment period.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Monotherapy - Day 22: Pre-dose | 1.374 mcg/mL | Geometric Coefficient of Variation 814.4 |
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: 1-3 hour postdose | 8.038 mcg/mL | Geometric Coefficient of Variation 38.24 |
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: Pre-dose | 1.848 mcg/mL | Geometric Coefficient of Variation 172.3 |
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Monotherapy - Day 1: Pre-dose | NA mcg/mL | — |
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Monotherapy - Day 22: 0.5-1 hour postdose | 7.212 mcg/mL | Geometric Coefficient of Variation 55.84 |
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: 0.5-1 hour postdose | 5.008 mcg/mL | Geometric Coefficient of Variation 74.54 |
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: 6-12 hour postdose | 5.186 mcg/mL | Geometric Coefficient of Variation 49.67 |
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Monotherapy - Day 1: 0.5-1 hour postdose | 3.647 mcg/mL | Geometric Coefficient of Variation 394.2 |
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: 3-6 hour postdose | 7.811 mcg/mL | Geometric Coefficient of Variation 38.68 |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Monotherapy - Day 1: 0.5-1 hour postdose | 2.093 mcg/mL | Geometric Coefficient of Variation 1217 |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: 3-6 hour postdose | 5.217 mcg/mL | Geometric Coefficient of Variation 51.57 |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: 1-3 hour postdose | 4.018 mcg/mL | Geometric Coefficient of Variation 155.6 |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Monotherapy - Day 1: Pre-dose | NA mcg/mL | — |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Monotherapy - Day 22: Pre-dose | 0.8500 mcg/mL | Geometric Coefficient of Variation 1501 |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Monotherapy - Day 22: 0.5-1 hour postdose | 5.370 mcg/mL | Geometric Coefficient of Variation 100.9 |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: Pre-dose | 0.6526 mcg/mL | Geometric Coefficient of Variation 847.8 |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: 6-12 hour postdose | 2.820 mcg/mL | Geometric Coefficient of Variation 60.56 |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: 0.5-1 hour postdose | 2.805 mcg/mL | Geometric Coefficient of Variation 234.2 |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: 3-6 hour postdose | 6.322 mcg/mL | Geometric Coefficient of Variation 43.84 |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: Pre-dose | 1.773 mcg/mL | Geometric Coefficient of Variation 92.68 |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Monotherapy - Day 1: 0.5-1 hour postdose | 5.016 mcg/mL | Geometric Coefficient of Variation 150.1 |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: 6-12 hour postdose | 3.661 mcg/mL | Geometric Coefficient of Variation 57.35 |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: 0.5-1 hour postdose | 4.288 mcg/mL | Geometric Coefficient of Variation 136.4 |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: 1-3 hour postdose | 5.897 mcg/mL | Geometric Coefficient of Variation 90.04 |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Monotherapy - Day 22: 0.5-1 hour postdose | 6.130 mcg/mL | Geometric Coefficient of Variation 144.9 |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Monotherapy - Day 1: Pre-dose | NA mcg/mL | — |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Monotherapy - Day 22: Pre-dose | 1.242 mcg/mL | Geometric Coefficient of Variation 534.6 |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: 1-3 hour postdose | 4.804 mcg/mL | Geometric Coefficient of Variation 57.38 |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Monotherapy - Day 1: Pre-dose | NA mcg/mL | — |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Monotherapy - Day 1: 0.5-1 hour postdose | 2.321 mcg/mL | Geometric Coefficient of Variation 291.7 |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Monotherapy - Day 22: Pre-dose | 2.053 mcg/mL | Geometric Coefficient of Variation 124.6 |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Monotherapy - Day 22: 0.5-1 hour postdose | 5.350 mcg/mL | Geometric Coefficient of Variation 75.21 |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: Pre-dose | 1.744 mcg/mL | Geometric Coefficient of Variation 103.7 |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: 0.5-1 hour postdose | 3.226 mcg/mL | Geometric Coefficient of Variation 60.08 |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: 3-6 hour postdose | 5.491 mcg/mL | Geometric Coefficient of Variation 35.36 |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: 6-12 hour postdose | 3.679 mcg/mL | Geometric Coefficient of Variation 52.8 |
| Second Stage: Ovarian Cancer Triplet | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: 0.5-1 hour postdose | 5.439 mcg/mL | Geometric Coefficient of Variation 70.73 |
| Second Stage: Ovarian Cancer Triplet | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: Pre-dose | 1.544 mcg/mL | Geometric Coefficient of Variation 102.3 |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: 3-6 hour postdose | 5.717 mcg/mL | Geometric Coefficient of Variation 57.3 |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: 0.5-1 hour postdose | 5.922 mcg/mL | Geometric Coefficient of Variation 98.89 |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: Pre-dose | 1.400 mcg/mL | Geometric Coefficient of Variation 423.2 |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: 6-12 hour postdose | 3.023 mcg/mL | Geometric Coefficient of Variation 74.63 |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: 1-3 hour postdose | 7.644 mcg/mL | Geometric Coefficient of Variation 55.09 |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: Pre-dose | 0.9718 mcg/mL | Geometric Coefficient of Variation 663.6 |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Combination therapy - Day 15: 0.5-1 hour postdose | 6.549 mcg/mL | Geometric Coefficient of Variation 72.47 |
Secondary
Initial and Second Stage Cohorts: Time to Study Treatment Discontinuation or Death (TDT)
The TDT was defined as the time from start of study treatment (Day 1; start of olaparib monotherapy for initial stage cohorts) to the earlier of the date of study treatment discontinuation or death. The TDT was calculated using the Kaplan-Meier technique.
Time frame: From baseline (Day 1) until treatment discontinuation/death. Assessed until DCO 14 Jun 2019 and 17 Sep 2021 for initial and second stage cohorts, respectively
Population: The full analysis set included all participants who received at least 1 dose of study treatment and had no important protocol deviation resulting in exclusion from the analysis set as defined in the Statistical Analysis Plan (i.e, not meeting key eligibility criteria).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Initial Stage: Small Cell Lung Cancer | Initial and Second Stage Cohorts: Time to Study Treatment Discontinuation or Death (TDT) | 2.8 months |
| Initial Stage: Breast Cancer | Initial and Second Stage Cohorts: Time to Study Treatment Discontinuation or Death (TDT) | 7.8 months |
| Initial Stage: Ovarian Cancer | Initial and Second Stage Cohorts: Time to Study Treatment Discontinuation or Death (TDT) | 13.1 months |
| Initial Stage: Gastric Cancer | Initial and Second Stage Cohorts: Time to Study Treatment Discontinuation or Death (TDT) | 2.8 months |
| Second Stage: Ovarian Cancer Triplet | Initial and Second Stage Cohorts: Time to Study Treatment Discontinuation or Death (TDT) | 19.3 months |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Time to Study Treatment Discontinuation or Death (TDT) | 15.9 months |
| Second Stage: Ovarian Cancer Doublet | Initial and Second Stage Cohorts: Time to Study Treatment Discontinuation or Death (TDT) | 6.6 months |
Secondary
Initial Stage Cohorts: DCR at Week 28
The DCR at 28 weeks was defined as the percentage of participants who had CR + PR + SD at 28 weeks. Participants demonstrated SD for a minimum interval of 27 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e. 189 days) following the start of treatment. The DCR was determined using Investigator assessments according to RECIST v1.1.
Time frame: RECIST performed at baseline, at 4 weeks after first dose of olaparib monotherapy and every 8 weeks +/-7 days thereafter. Assessed until DCO 14 Jun 2019.
Population: The full analysis set included all participants who received at least 1 dose of study treatment and had no important protocol deviation resulting in exclusion from the analysis set as defined in the Statistical Analysis Plan (i.e, not meeting key eligibility criteria).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Initial Stage: Small Cell Lung Cancer | Initial Stage Cohorts: DCR at Week 28 | 5.3 percentage of participants |
| Initial Stage: Breast Cancer | Initial Stage Cohorts: DCR at Week 28 | 50.0 percentage of participants |
| Initial Stage: Ovarian Cancer | Initial Stage Cohorts: DCR at Week 28 | 65.6 percentage of participants |
| Initial Stage: Gastric Cancer | Initial Stage Cohorts: DCR at Week 28 | 7.7 percentage of participants |
Secondary
Initial Stage Cohorts: Percentage Change From Baseline in Target Tumor Size at Weeks 12 and 28
The percentage change in target tumor size at each timepoint (based on RECIST 1.1 target lesion measurements) was obtained for each participant taking the difference between the sum of the target lesions at each timepoint and the sum of the target lesions at baseline divided by the sum of the target lesions at baseline times 100. Baseline was defined as the last evaluable assessment prior to starting olaparib treatment.
Time frame: Baseline (Day 1) and Weeks 12 and 28. Assessed until DCO 14 Jun 2019
Population: The full analysis set included all participants who received at least 1 dose of study treatment and had no important protocol deviation resulting in exclusion from the analysis set as defined in the Statistical Analysis Plan (i.e, not meeting key eligibility criteria). Only participants with either a tumor size recorded at 12 and 28 weeks or enough information to impute a value were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Initial Stage: Small Cell Lung Cancer | Initial Stage Cohorts: Percentage Change From Baseline in Target Tumor Size at Weeks 12 and 28 | Week 12 | 17.23 percentage change in tumor size | Standard Deviation 54.752 |
| Initial Stage: Small Cell Lung Cancer | Initial Stage Cohorts: Percentage Change From Baseline in Target Tumor Size at Weeks 12 and 28 | Week 28 | -2.05 percentage change in tumor size | Standard Deviation 15.671 |
| Initial Stage: Breast Cancer | Initial Stage Cohorts: Percentage Change From Baseline in Target Tumor Size at Weeks 12 and 28 | Week 28 | -40.85 percentage change in tumor size | Standard Deviation 39.541 |
| Initial Stage: Breast Cancer | Initial Stage Cohorts: Percentage Change From Baseline in Target Tumor Size at Weeks 12 and 28 | Week 12 | -26.13 percentage change in tumor size | Standard Deviation 43.033 |
| Initial Stage: Ovarian Cancer | Initial Stage Cohorts: Percentage Change From Baseline in Target Tumor Size at Weeks 12 and 28 | Week 12 | -35.86 percentage change in tumor size | Standard Deviation 29.791 |
| Initial Stage: Ovarian Cancer | Initial Stage Cohorts: Percentage Change From Baseline in Target Tumor Size at Weeks 12 and 28 | Week 28 | -53.74 percentage change in tumor size | Standard Deviation 31.147 |
| Initial Stage: Gastric Cancer | Initial Stage Cohorts: Percentage Change From Baseline in Target Tumor Size at Weeks 12 and 28 | Week 12 | 20.81 percentage change in tumor size | Standard Deviation 75.944 |
| Initial Stage: Gastric Cancer | Initial Stage Cohorts: Percentage Change From Baseline in Target Tumor Size at Weeks 12 and 28 | Week 28 | -41.00 percentage change in tumor size | Standard Deviation 43.625 |
Secondary
Second Stage Cohorts: DCR at Week 56
The DCR at 56 weeks was defined as the percentage of participants who had CR + PR + SD at 56 weeks. Participants demonstrated SD for a minimum interval of 55 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e. 385 days) following the start of treatment. The DCR was determined using Investigator assessments according to RECIST v1.1.
Time frame: RECIST performed at baseline, and every 8 weeks +/-7 days thereafter. Assessed until 17 Sep 2021.
Population: The full analysis set included all participants who received at least 1 dose of study treatment and had no important protocol deviation resulting in exclusion from the analysis set as defined in the Statistical Analysis Plan (i.e, not meeting key eligibility criteria).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Initial Stage: Small Cell Lung Cancer | Second Stage Cohorts: DCR at Week 56 | 41.2 percentage of participants |
| Initial Stage: Breast Cancer | Second Stage Cohorts: DCR at Week 56 | 38.7 percentage of participants |
| Initial Stage: Ovarian Cancer | Second Stage Cohorts: DCR at Week 56 | 9.4 percentage of participants |
Secondary
Second Stage Cohort: Serum Concentrations of Bevacizumab
Blood samples were collected to determine the serum concentration of bevacizumab.
Time frame: Pre-dose and within 10 minutes of end of infusion on Days 1 and 85; Pre-dose on Days 29 and 169; and 90 days post last dose of bevacizumab. Assessed until DCO 17 Sep 2021
Population: The bevacizumab PK analysis set included all participants who received at least 1 dose of bevacizumab and provided any post-dose evaluable bevacizumab PK concentration.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Initial Stage: Small Cell Lung Cancer | Second Stage Cohort: Serum Concentrations of Bevacizumab | Day 1: Pre-dose | NA mcg/mL | — |
| Initial Stage: Small Cell Lung Cancer | Second Stage Cohort: Serum Concentrations of Bevacizumab | Day 1: End of infusion | 243.7 mcg/mL | Geometric Coefficient of Variation 30.01 |
| Initial Stage: Small Cell Lung Cancer | Second Stage Cohort: Serum Concentrations of Bevacizumab | Day 29: Pre-dose | 104.6 mcg/mL | Geometric Coefficient of Variation 29.3 |
| Initial Stage: Small Cell Lung Cancer | Second Stage Cohort: Serum Concentrations of Bevacizumab | Day 85: Pre-dose | 145.5 mcg/mL | Geometric Coefficient of Variation 28.26 |
| Initial Stage: Small Cell Lung Cancer | Second Stage Cohort: Serum Concentrations of Bevacizumab | Day 85: End of infusion | 364.0 mcg/mL | Geometric Coefficient of Variation 23.74 |
| Initial Stage: Small Cell Lung Cancer | Second Stage Cohort: Serum Concentrations of Bevacizumab | Day 169: Pre-dose | 147.9 mcg/mL | Geometric Coefficient of Variation 118 |
| Initial Stage: Small Cell Lung Cancer | Second Stage Cohort: Serum Concentrations of Bevacizumab | 90 days post last dose | 5.094 mcg/mL | Geometric Coefficient of Variation 224.1 |
Secondary
Second Stage Cohorts: Percentage Change From Baseline in Target Tumor Size at Weeks 24 and 56
The percentage change in target tumor size at each timepoint (based on RECIST 1.1 target lesion measurements) was obtained for each participant taking the difference between the sum of the target lesions at each timepoint and the sum of the target lesions at baseline divided by the sum of the target lesions at baseline times 100. Baseline was defined as the last assessment prior to Cycle 1 Day 1.
Time frame: Baseline (Day 1) and Weeks 24 and 56. Assessed until DCO 17 Sep 2021
Population: The full analysis set included all participants who received at least 1 dose of study treatment and had no important protocol deviation resulting in exclusion from the analysis set as defined in the Statistical Analysis Plan (i.e, not meeting key eligibility criteria). Only participants with either a tumor size recorded at 24 and 56 weeks or enough information to impute a value were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Initial Stage: Small Cell Lung Cancer | Second Stage Cohorts: Percentage Change From Baseline in Target Tumor Size at Weeks 24 and 56 | Week 24 | -66.30 percentage change in tumor size | Standard Deviation 26.672 |
| Initial Stage: Small Cell Lung Cancer | Second Stage Cohorts: Percentage Change From Baseline in Target Tumor Size at Weeks 24 and 56 | Week 56 | -77.74 percentage change in tumor size | Standard Deviation 26.472 |
| Initial Stage: Breast Cancer | Second Stage Cohorts: Percentage Change From Baseline in Target Tumor Size at Weeks 24 and 56 | Week 24 | -43.00 percentage change in tumor size | Standard Deviation 32.432 |
| Initial Stage: Breast Cancer | Second Stage Cohorts: Percentage Change From Baseline in Target Tumor Size at Weeks 24 and 56 | Week 56 | -60.00 percentage change in tumor size | Standard Deviation 29.058 |
| Initial Stage: Ovarian Cancer | Second Stage Cohorts: Percentage Change From Baseline in Target Tumor Size at Weeks 24 and 56 | Week 24 | -35.63 percentage change in tumor size | Standard Deviation 34.001 |
| Initial Stage: Ovarian Cancer | Second Stage Cohorts: Percentage Change From Baseline in Target Tumor Size at Weeks 24 and 56 | Week 56 | -39.54 percentage change in tumor size | Standard Deviation 33.719 |
Secondary
Second Stage Expansion Cohort: DCR at Week 24
The DCR at 24 weeks was defined as the percentage of participants who had CR + PR + SD at 24 weeks. Participants demonstrated SD for a minimum interval of 23 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e. 161 days) following the start of treatment. The DCR was determined using Investigator assessments according to RECIST v1.1.
Time frame: RECIST performed at baseline, and every 8 weeks +/-7 days thereafter. Assessed until 17 Sep 2021.
Population: The full analysis set included all participants who received at least 1 dose of study treatment and had no important protocol deviation resulting in exclusion from the analysis set as defined in the Statistical Analysis Plan (i.e, not meeting key eligibility criteria).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Initial Stage: Small Cell Lung Cancer | Second Stage Expansion Cohort: DCR at Week 24 | 88.2 percentage of participants |