Fallopian Tube Cancer, Ovarian Cancer, Peritoneal Cancer
Conditions
Keywords
Platinum-resistant, Antibody drug conjugate, Tisotumab vedotin, PROC, Seattle Genetics
Brief summary
This trial will study tisotumab vedotin to find out what its side effects are and to see if it works for platinum-resistant ovarian cancer (PROC). It will test different doses of tisotumab vedotin that are given at different times. It will also compare the side effects and ability to treat tumors of these different doses and schedules. In this study, there will be a safety run-in group of approximately 12 patients that will look at a dose-dense treatment schedule. In a dose-dense schedule, smaller doses are given more frequently. In addition to the safety run-in patients, there will be three groups in the study. One group will get tisotumab vedotin once every 3 weeks (21-day cycles). The two other groups will get tisotumab vedotin once a week for 3 weeks followed by 1 week off (28-day cycles).
Detailed description
The study objectives are to evaluate the safety, antitumor activity, and pharmacokinetics of tisotumab vedotin (TV) administered every 3 weeks or on Days 1, 8, and 15 of every 4-week cycle (3Q4W) for patients with epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer that has relapsed within 6 months of the completion of platinum-based treatment and determined to be platinum resistant. All patients must have PROC and be eligible for single agent chemotherapy. The safety run-in period will evaluate the safety of a weekly schedule. The highest dose level that is considered safe will be the recommended phase 2 dose (RP2D) and will be used in Part A. In Part A, participants will be randomized in a 1:1 ratio to receive tisotumab vedotin intravenously (IV) every 3 weeks (Q3W regimen) or the safety run-in RP2D on Days 1, 8, and 15 of every 4-week cycle (weekly regimen; 3Q4W) if a RP2D has been identified. Participants who enroll in Part B will receive tisotumab vedotin on Days 1, 8, and 15 of every 4-week cycle (weekly regimen) at a pre-specified dose level, if the dose level is considered safe and tolerable in the safety run-in period.
Interventions
Intravenous (IV) infusion
Sponsors
Genmab
Seagen Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologic documentation of epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer * Safety run-in only: PROC. Patients may have received more than 1 prior systemic treatment regimen in the PROC setting. * Part A and Part B only: Patients with PROC who have received 1 to 3 anticancer lines of therapy overall, including at least 1 line of therapy containing bevacizumab or biosimilar. * Adjuvant ± neoadjuvant are considered 1 line of therapy. * Patients may have received a PARP inhibitor or an immuno-oncology (IO) agent; any of these regimens are to be considered a line of therapy for the purposes of this study if not used as maintenance therapy. * Maintenance therapy (including bevacizumab, PARP inhibitors and IOs) will be considered part of the preceding line of therapy and not to be counted as a new line of therapy. * Any chemotherapy regimen change due to toxicity in the absence of disease progression is considered as part of the same line of therapy. * Hormonal therapy will be not be counted towards the lines of therapy. * Measurable disease according to RECIST v1.1 as assessed by the investigator * An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1 * Life expectancy of at least 3 months * Able to provide fresh or archival tissue for biomarker analysis
Exclusion criteria
* Primary platinum-refractory disease, defined as disease progression within 2 months of completion of first line platinum-based therapy * Patients with clinical symptoms or signs of gastrointestinal obstruction with the past 6 months or who currently require parenteral nutrition * Hematological: Known past or current coagulation defects leading to an increased risk of bleeding, diffuse alveolar hemorrhage from vasculitis, known bleeding diathesis, ongoing major bleeding, or trauma with increased risk of life-threatening bleeding within 8 weeks of trial entry * Cardiovascular: Clinically significant cardiac disease including uncontrolled hypertension, unstable angina, acute myocardial infarction with 6 months of screening, serious cardiac arrhythmia requiring medication, medical history of congestive heart failure, or medical history of decreased cardiac ejection fraction of \<45% * Ophthalmological: Active ocular surface disease at baseline or prior episode of cicatricial conjunctivitis or Stevens Johnson syndrome * Prior treatment with MMAE-derived drugs * Inflammatory bowel disease including Crohn's disease and ulcerative colitis * Ongoing, acute, or chronic inflammatory skin disease * Uncontrolled tumor-related pain * Inflammatory lung disease requiring chronic medical therapy * Grade 3 or higher pulmonary disease unrelated to underlying malignancy * Uncontrolled pleural or pericardial effusions * Grade \>1 peripheral neuropathy * Patients who are pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Objective Response Rate (ORR) (Part B) | Up to 9.7 months | Proportion of participants who achieve a confirmed complete response (CR) or partial response (PR) according to RECIST v1.1 as assessed by the investigator |
| Number of Participants With Dose-Limiting Toxicities (DLTs) (Safety Run-In Only) | Up to 28 days | Incidence of dose-limiting toxicity (DLT) was evaluated in participants enrolled in the Safety Run-In, who were followed for protocol-defined DLT events up to 28 days after the first dose of tisotumab vedotin. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cancer Antigen 125 (CA-125) Response Rate According to Gynecologic Cancer Intergroup (GCIG) Criteria (Part B) | Up to 10.1 months | Percentage of participants who have at least a 50% reduction in CA-125 value from baseline |
| Overall Response According to the Gynecological Cancer Intergroup (GCIG) Combined RECIST and CA-125 Criteria (Part B) | Up to 10.1 months | Percentage of participants whose best response is a CR or PR according to the GCIG combined RECIST and CA-125 criteria |
| Duration of Response (DOR) (Part B) | Up to 8.3 months | Time from the first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of PD or death due to any cause, whichever comes first |
| Disease Control Rate (DCR) (Part B) | Up to 3.0 months | Percentage of participants who achieved a confirmed Complete Response(CR) or Partial Response (PR) per RECIST v1.1 as assessed by the investigator, or meet the Stable Disease (SD) criteria at least once after start of study treatment at a minimum interval of 12 weeks. |
| Time to Response (TTR) (Part B) | Up to 23.0 months | Time from the start of study treatment to the first documentation of objective response (CR or PR that is subsequently confirmed) |
| Progression-free Survival (PFS) (Part B) | Up to 9.7 months | Time from the start of study treatment to the first documentation of PD or death due to any cause, whichever comes first |
| Overall Survival (OS) (Part B) | Up to 23.0 months | Time from the start of study treatment to date of death due to any cause |
| Incidence of Antitherapeutic Antibodies (ATA) (Part B) | Up to 6.9 months | The proportion of participants who develop ATA at any time during the study. A positive baseline ATA result is considered positive post-baseline if the post-baseline ATA titer result is at least four times higher than the baseline result. |
| Pharmacokinetic (PK) Parameter: Antibody-Drug Conjugate (ADC) Maximum Concentration (Cmax) (Part B) | Samples for PK measures were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle. | ADC Cmax was derived from the PK blood samples collected. |
| Number of Participants With Adverse Events (AEs) (Part B) | Up to 23.0 months | An AE is any untoward medical occurrence in a patient or clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. Treatment emergent AEs (TEAEs) are defined as events that are new or worsened on or after receiving the first dose of study treatment and up through 30 days after the last dose of study treatment. |
| PK Parameter: ADC Area Under Concentration-Time Curve (AUC) (Part B) | Cycle 1 Dose 1 AUC 7: Assessed from Cycle 1 Days 1 - 8 (predose). Cycle 1 Dose 3 AUC 7: Assessed from Cycle 1 Days 15 - 22. Cycle 1 Dose 3 AUC 14: Assessed from Cycle 1 Days 15 - Cycle 2 Day 1 (predose). | ADC AUC was derived from the PK blood samples collected. |
| PK Parameter: Free Monomethyl Auristatin E (MMAE) Cmax (Part B) | Samples for PK measures were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle. | MMAE Cmax was derived from the PK blood samples collected. |
| PK Parameter: MMAE Tmax (Part B) | Samples for PK measures were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle. | MMAE Tmax was derived from the PK blood samples collected. |
| PK Parameter: MMAE AUC (Part B) | Samples for PK measures were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle. | MMAE AUC was derived from the PK blood samples collected. |
| PK Parameter: MMAE Trough Concentration (Ctrough) (Part B) | Samples for PK measures were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle. | MMAE Ctrough was derived from the PK blood samples collected. |
| PK Parameter: Total Antibody (TAb) Cmax (Part B) | Samples for PK measures were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle. | TAb Cmax was derived from the PK blood samples collected. |
| PK Parameter: TAb Tmax (Part B) | Samples for PK measures were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle. | TAb Tmax was derived from the PK blood samples collected. |
| PK Parameter: TAb Area Under Concentration-Time Curve (AUC) (Part B) | Cycle 1 Dose 1 AUC 7: Assessed from Cycle 1 Days 1 - 8 (predose). Cycle 1 Dose 3 AUC 7: Assessed from Cycle 1 Days 15 - 22. Cycle 1 Dose 3 AUC 14: Assessed from Cycle 1 Days 15 - Cycle 2 Day 1 (predose). | TAb AUC was derived from the PK blood samples collected. |
| PK Parameter: ADC Time of Cmax (Tmax) (Part B) | Samples for PK measures were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle. | ADC Tmax was derived from the PK blood samples collected. |
| Confirmed and Unconfirmed ORR (Part B) | Up to 9.7 months | Proportion of participants who achieve a CR or PR according to RECIST v1.1 as assessed by the investigator |
Countries
Belgium, Denmark, Ireland, Italy, Spain, United States
Participant flow
Recruitment details
A total of 98 participants were enrolled into the Safety Run-In and Part B Expansion cohorts, of which 94 received study drug. No participants were enrolled into Part A.
Participants by arm
| Arm | Count |
|---|---|
| Safety Run-In 0.9 mg/kg 3Q4W Tisotumab Vedotin 0.9 mg/kg by IV infusion on Days 1, 8, and 15 of every 4-week cycle | 7 |
| Safety Run-In 1.2 mg/kg 3Q4W Tisotumab Vedotin 1.2 mg/kg by IV infusion on Days 1, 8, and 15 of every 4-week cycle | 8 |
| Part B Expansion Tisotumab Vedotin 0.9 mg/kg by IV infusion on Days 1, 8, and 15 of every 4-week cycle | 79 |
| Total | 94 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 2 |
| Overall Study | Death | 6 | 5 | 0 | 0 | 53 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 4 |
| Overall Study | Met exclusion criteria after enrollment | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Study closure by Sponsor | 0 | 2 | 0 | 0 | 17 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 0 | 0 | 4 |
| Overall Study | Withdrawal - declined follow-up | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal - subsequent treatment | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Safety Run-In 1.2 mg/kg 3Q4W | Part B Expansion | Total | Safety Run-In 0.9 mg/kg 3Q4W |
|---|---|---|---|---|
| Age, Continuous | 67.5 Years | 60.0 Years | 62.0 Years | 69.0 Years |
| Eastern Cooperative Oncology Group (ECOG) Performance Score Grade 0 | 5 Participants | 48 Participants | 57 Participants | 4 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Score Grade 1 | 3 Participants | 31 Participants | 37 Participants | 3 Participants |
| Race/Ethnicity, Customized Hispanic or Latino/a, or of Spanish Origin | 1 Participants | 9 Participants | 10 Participants | 0 Participants |
| Race/Ethnicity, Customized Not of Hispanic or Latino/a, or of Spanish Origin | 7 Participants | 69 Participants | 82 Participants | 6 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 4 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 6 Participants | 7 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 6 Participants | 69 Participants | 81 Participants | 6 Participants |
| Sex/Gender, Customized Female | 8 Participants | 79 Participants | 94 Participants | 7 Participants |
| Sex/Gender, Customized Intersex | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 8 | 5 / 8 | 53 / 82 |
| other Total, other adverse events | 7 / 7 | 8 / 8 | 77 / 79 |
| serious Total, serious adverse events | 2 / 7 | 4 / 8 | 28 / 79 |
Outcome results
Primary
Confirmed Objective Response Rate (ORR) (Part B)
Proportion of participants who achieve a confirmed complete response (CR) or partial response (PR) according to RECIST v1.1 as assessed by the investigator
Time frame: Up to 9.7 months
Population: The Full Analysis Set includes all participants who received any amount of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Safety Run-In 0.9 mg/kg 3Q4W | Confirmed Objective Response Rate (ORR) (Part B) | 7 Participants |
Primary
Number of Participants With Dose-Limiting Toxicities (DLTs) (Safety Run-In Only)
Incidence of dose-limiting toxicity (DLT) was evaluated in participants enrolled in the Safety Run-In, who were followed for protocol-defined DLT events up to 28 days after the first dose of tisotumab vedotin.
Time frame: Up to 28 days
Population: Participants from the Safety Analysis Set that were enrolled in the Safety Run-In. The Safety Analysis Set includes all participants who received any amount of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Safety Run-In 0.9 mg/kg 3Q4W | Number of Participants With Dose-Limiting Toxicities (DLTs) (Safety Run-In Only) | 0 Participants |
| Safety Run-In 1.2 mg/kg 3Q4W | Number of Participants With Dose-Limiting Toxicities (DLTs) (Safety Run-In Only) | 1 Participants |
Secondary
Cancer Antigen 125 (CA-125) Response Rate According to Gynecologic Cancer Intergroup (GCIG) Criteria (Part B)
Percentage of participants who have at least a 50% reduction in CA-125 value from baseline
Time frame: Up to 10.1 months
Population: The CA-125 evaluable analysis set includes participants who have an elevated baseline CA-125 value of ≥2 x ULN (upper limit of normal) within 2 weeks prior to the first dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Run-In 0.9 mg/kg 3Q4W | Cancer Antigen 125 (CA-125) Response Rate According to Gynecologic Cancer Intergroup (GCIG) Criteria (Part B) | 12.0 Percentage of Participants |
Secondary
Confirmed and Unconfirmed ORR (Part B)
Proportion of participants who achieve a CR or PR according to RECIST v1.1 as assessed by the investigator
Time frame: Up to 9.7 months
Population: The Full Analysis Set includes all participants who received any amount of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Run-In 0.9 mg/kg 3Q4W | Confirmed and Unconfirmed ORR (Part B) | 18.0 Percentage of Participants |
Secondary
Disease Control Rate (DCR) (Part B)
Percentage of participants who achieved a confirmed Complete Response(CR) or Partial Response (PR) per RECIST v1.1 as assessed by the investigator, or meet the Stable Disease (SD) criteria at least once after start of study treatment at a minimum interval of 12 weeks.
Time frame: Up to 3.0 months
Population: The Full Analysis Set includes all participants who received any amount of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Run-In 0.9 mg/kg 3Q4W | Disease Control Rate (DCR) (Part B) | 54.4 Percentage of Participants |
Secondary
Duration of Response (DOR) (Part B)
Time from the first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of PD or death due to any cause, whichever comes first
Time frame: Up to 8.3 months
Population: Subset of the Full Analysis Set includes all participants who received any amount of study drug and had a confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Run-In 0.9 mg/kg 3Q4W | Duration of Response (DOR) (Part B) | 4.21 Months |
Secondary
Incidence of Antitherapeutic Antibodies (ATA) (Part B)
The proportion of participants who develop ATA at any time during the study. A positive baseline ATA result is considered positive post-baseline if the post-baseline ATA titer result is at least four times higher than the baseline result.
Time frame: Up to 6.9 months
Population: Participants in the Safety Analysis Set with a baseline and at least one post-baseline ATA sample.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Safety Run-In 0.9 mg/kg 3Q4W | Incidence of Antitherapeutic Antibodies (ATA) (Part B) | Baseline Negative - Negative post-baseline | 65 Participants |
| Safety Run-In 0.9 mg/kg 3Q4W | Incidence of Antitherapeutic Antibodies (ATA) (Part B) | Baseline Negative - Positive post-baseline | 3 Participants |
| Safety Run-In 0.9 mg/kg 3Q4W | Incidence of Antitherapeutic Antibodies (ATA) (Part B) | Baseline Positive - Negative post-baseline | 3 Participants |
| Safety Run-In 0.9 mg/kg 3Q4W | Incidence of Antitherapeutic Antibodies (ATA) (Part B) | Baseline Positive - Positive post-baseline | 0 Participants |
Secondary
Number of Participants With Adverse Events (AEs) (Part B)
An AE is any untoward medical occurrence in a patient or clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. Treatment emergent AEs (TEAEs) are defined as events that are new or worsened on or after receiving the first dose of study treatment and up through 30 days after the last dose of study treatment.
Time frame: Up to 23.0 months
Population: The Safety Analysis Set includes all participants who received any amount of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Safety Run-In 0.9 mg/kg 3Q4W | Number of Participants With Adverse Events (AEs) (Part B) | Any TEAE | 79 Participants |
| Safety Run-In 0.9 mg/kg 3Q4W | Number of Participants With Adverse Events (AEs) (Part B) | Treatment-related TEAE | 67 Participants |
| Safety Run-In 0.9 mg/kg 3Q4W | Number of Participants With Adverse Events (AEs) (Part B) | Treatment-related Grade 3-4 TEAE | 14 Participants |
| Safety Run-In 0.9 mg/kg 3Q4W | Number of Participants With Adverse Events (AEs) (Part B) | Treatment-related Grade 5 TEAE | 0 Participants |
| Safety Run-In 0.9 mg/kg 3Q4W | Number of Participants With Adverse Events (AEs) (Part B) | Max severity of TEAE - Grade 1 | 7 Participants |
| Safety Run-In 0.9 mg/kg 3Q4W | Number of Participants With Adverse Events (AEs) (Part B) | Max severity of TEAE - Grade 2 | 35 Participants |
| Safety Run-In 0.9 mg/kg 3Q4W | Number of Participants With Adverse Events (AEs) (Part B) | Max severity of TEAE - Grade 3 | 32 Participants |
| Safety Run-In 0.9 mg/kg 3Q4W | Number of Participants With Adverse Events (AEs) (Part B) | Max severity of TEAE - Grade 4 | 3 Participants |
| Safety Run-In 0.9 mg/kg 3Q4W | Number of Participants With Adverse Events (AEs) (Part B) | Max severity of TEAE - Grade 5 | 2 Participants |
| Safety Run-In 0.9 mg/kg 3Q4W | Number of Participants With Adverse Events (AEs) (Part B) | Any treatment-emergent serious AE (SAE) | 28 Participants |
| Safety Run-In 0.9 mg/kg 3Q4W | Number of Participants With Adverse Events (AEs) (Part B) | Treatment-related SAE | 6 Participants |
Secondary
Overall Response According to the Gynecological Cancer Intergroup (GCIG) Combined RECIST and CA-125 Criteria (Part B)
Percentage of participants whose best response is a CR or PR according to the GCIG combined RECIST and CA-125 criteria
Time frame: Up to 10.1 months
Population: The Full Analysis Set includes all participants who received any amount of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Run-In 0.9 mg/kg 3Q4W | Overall Response According to the Gynecological Cancer Intergroup (GCIG) Combined RECIST and CA-125 Criteria (Part B) | 11.0 Percentage of Participants |
Secondary
Overall Survival (OS) (Part B)
Time from the start of study treatment to date of death due to any cause
Time frame: Up to 23.0 months
Population: The Full Analysis Set includes all participants who received any amount of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Run-In 0.9 mg/kg 3Q4W | Overall Survival (OS) (Part B) | 10.68 Months |
Secondary
Pharmacokinetic (PK) Parameter: Antibody-Drug Conjugate (ADC) Maximum Concentration (Cmax) (Part B)
ADC Cmax was derived from the PK blood samples collected.
Time frame: Samples for PK measures were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle.
Population: PK analysis set which includes enrolled participants who received any amount of study drug and at least one PK parameter can be estimated.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-In 0.9 mg/kg 3Q4W | Pharmacokinetic (PK) Parameter: Antibody-Drug Conjugate (ADC) Maximum Concentration (Cmax) (Part B) | Cycle 1, Dose 1 | 20.582 µg/mL | Geometric Coefficient of Variation 26.963 |
| Safety Run-In 0.9 mg/kg 3Q4W | Pharmacokinetic (PK) Parameter: Antibody-Drug Conjugate (ADC) Maximum Concentration (Cmax) (Part B) | Cycle 1, Dose 3 | 21.817 µg/mL | Geometric Coefficient of Variation 26.823 |
Secondary
PK Parameter: ADC Area Under Concentration-Time Curve (AUC) (Part B)
ADC AUC was derived from the PK blood samples collected.
Time frame: Cycle 1 Dose 1 AUC 7: Assessed from Cycle 1 Days 1 - 8 (predose). Cycle 1 Dose 3 AUC 7: Assessed from Cycle 1 Days 15 - 22. Cycle 1 Dose 3 AUC 14: Assessed from Cycle 1 Days 15 - Cycle 2 Day 1 (predose).
Population: PK Analysis Set includes enrolled participants who received any amount of study drug and at least one PK parameter can be estimated.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-In 0.9 mg/kg 3Q4W | PK Parameter: ADC Area Under Concentration-Time Curve (AUC) (Part B) | Cycle 1, Dose 1 - AUC 7 Days-ADC | 25.198 µg/mL*day | Geometric Coefficient of Variation 25.335 |
| Safety Run-In 0.9 mg/kg 3Q4W | PK Parameter: ADC Area Under Concentration-Time Curve (AUC) (Part B) | Cycle 1, Dose 3 - AUC 7 Days-ADC | 30.159 µg/mL*day | Geometric Coefficient of Variation 32.261 |
| Safety Run-In 0.9 mg/kg 3Q4W | PK Parameter: ADC Area Under Concentration-Time Curve (AUC) (Part B) | Cycle 1, Dose 3 - AUC 14 Days-ADC | 31.716 µg/mL*day | Geometric Coefficient of Variation 31.632 |
Secondary
PK Parameter: ADC Time of Cmax (Tmax) (Part B)
ADC Tmax was derived from the PK blood samples collected.
Time frame: Samples for PK measures were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle.
Population: PK analysis set which includes enrolled participants who received any amount of study drug and at least one PK parameter can be estimated.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-In 0.9 mg/kg 3Q4W | PK Parameter: ADC Time of Cmax (Tmax) (Part B) | Cycle 1, Dose 1 | 0.041 Days | Geometric Coefficient of Variation 53.112 |
| Safety Run-In 0.9 mg/kg 3Q4W | PK Parameter: ADC Time of Cmax (Tmax) (Part B) | Cycle 1, Dose 3 | 0.041 Days | Geometric Coefficient of Variation 78.407 |
Secondary
PK Parameter: Free Monomethyl Auristatin E (MMAE) Cmax (Part B)
MMAE Cmax was derived from the PK blood samples collected.
Time frame: Samples for PK measures were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle.
Population: PK analysis set which includes enrolled participants who received any amount of study drug and at least one PK parameter can be estimated.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-In 0.9 mg/kg 3Q4W | PK Parameter: Free Monomethyl Auristatin E (MMAE) Cmax (Part B) | Cycle 1, Dose 1 | 1.778 ng/mL | Geometric Coefficient of Variation 66.636 |
| Safety Run-In 0.9 mg/kg 3Q4W | PK Parameter: Free Monomethyl Auristatin E (MMAE) Cmax (Part B) | Cycle 1, Dose 3 | 2.552 ng/mL | Geometric Coefficient of Variation 52.442 |
Secondary
PK Parameter: MMAE AUC (Part B)
MMAE AUC was derived from the PK blood samples collected.
Time frame: Samples for PK measures were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle.
Population: PK Analysis Set includes enrolled participants who received any amount of study drug and at least one PK parameter can be estimated.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-In 0.9 mg/kg 3Q4W | PK Parameter: MMAE AUC (Part B) | Cycle 1, Dose 1 - AUC Last-MMAE | 8.709 ng/mL*day | Geometric Coefficient of Variation 63.747 |
| Safety Run-In 0.9 mg/kg 3Q4W | PK Parameter: MMAE AUC (Part B) | Cycle 1, Dose 3 - AUC Last-MMAE | 16.578 ng/mL*day | Geometric Coefficient of Variation 52.121 |
Secondary
PK Parameter: MMAE Tmax (Part B)
MMAE Tmax was derived from the PK blood samples collected.
Time frame: Samples for PK measures were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle.
Population: PK analysis set which includes enrolled participants who received any amount of study drug and at least one PK parameter can be estimated.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-In 0.9 mg/kg 3Q4W | PK Parameter: MMAE Tmax (Part B) | Cycle 1, Dose 1 | 2.061 Days | Geometric Coefficient of Variation 26.838 |
| Safety Run-In 0.9 mg/kg 3Q4W | PK Parameter: MMAE Tmax (Part B) | Cycle 1, Dose 3 | 2.101 Days | Geometric Coefficient of Variation 28.82 |
Secondary
PK Parameter: MMAE Trough Concentration (Ctrough) (Part B)
MMAE Ctrough was derived from the PK blood samples collected.
Time frame: Samples for PK measures were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle.
Population: PK analysis set which includes enrolled participants who received any amount of study drug and at least one PK parameter can be estimated.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Safety Run-In 0.9 mg/kg 3Q4W | PK Parameter: MMAE Trough Concentration (Ctrough) (Part B) | 0.230 ng/mL | Geometric Coefficient of Variation 82.638 |
Secondary
PK Parameter: TAb Area Under Concentration-Time Curve (AUC) (Part B)
TAb AUC was derived from the PK blood samples collected.
Time frame: Cycle 1 Dose 1 AUC 7: Assessed from Cycle 1 Days 1 - 8 (predose). Cycle 1 Dose 3 AUC 7: Assessed from Cycle 1 Days 15 - 22. Cycle 1 Dose 3 AUC 14: Assessed from Cycle 1 Days 15 - Cycle 2 Day 1 (predose).
Population: PK Analysis Set includes enrolled participants who received any amount of study drug and at least one PK parameter can be estimated.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-In 0.9 mg/kg 3Q4W | PK Parameter: TAb Area Under Concentration-Time Curve (AUC) (Part B) | Cycle 1, Dose 1 - AUC 7 Days-TAb | 35.535 µg/mL*day | Geometric Coefficient of Variation 24.95 |
| Safety Run-In 0.9 mg/kg 3Q4W | PK Parameter: TAb Area Under Concentration-Time Curve (AUC) (Part B) | Cycle 1, Dose 3 - AUC 7 Days-TAb | 39.371 µg/mL*day | Geometric Coefficient of Variation 29.218 |
| Safety Run-In 0.9 mg/kg 3Q4W | PK Parameter: TAb Area Under Concentration-Time Curve (AUC) (Part B) | Cycle 1, Dose 3 - AUC 14 Days-TAb | 42.240 µg/mL*day | Geometric Coefficient of Variation 29.206 |
Secondary
PK Parameter: TAb Tmax (Part B)
TAb Tmax was derived from the PK blood samples collected.
Time frame: Samples for PK measures were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle.
Population: PK analysis set which includes enrolled participants who received any amount of study drug and at least one PK parameter can be estimated.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-In 0.9 mg/kg 3Q4W | PK Parameter: TAb Tmax (Part B) | Cycle 1, Dose 3 | 0.043 Days | Geometric Coefficient of Variation 67.795 |
| Safety Run-In 0.9 mg/kg 3Q4W | PK Parameter: TAb Tmax (Part B) | Cycle 1, Dose 1 | 0.041 Days | Geometric Coefficient of Variation 67.072 |
Secondary
PK Parameter: Total Antibody (TAb) Cmax (Part B)
TAb Cmax was derived from the PK blood samples collected.
Time frame: Samples for PK measures were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle.
Population: PK analysis set which includes enrolled participants who received any amount of study drug and at least one PK parameter can be estimated.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-In 0.9 mg/kg 3Q4W | PK Parameter: Total Antibody (TAb) Cmax (Part B) | Cycle 1, Dose 1 | 18.418 ng/mL | Geometric Coefficient of Variation 28.631 |
| Safety Run-In 0.9 mg/kg 3Q4W | PK Parameter: Total Antibody (TAb) Cmax (Part B) | Cycle 1, Dose 3 | 19.955 ng/mL | Geometric Coefficient of Variation 28.405 |
Secondary
Progression-free Survival (PFS) (Part B)
Time from the start of study treatment to the first documentation of PD or death due to any cause, whichever comes first
Time frame: Up to 9.7 months
Population: The Full Analysis Set includes all participants who received any amount of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Run-In 0.9 mg/kg 3Q4W | Progression-free Survival (PFS) (Part B) | 2.73 Months |
Secondary
Time to Response (TTR) (Part B)
Time from the start of study treatment to the first documentation of objective response (CR or PR that is subsequently confirmed)
Time frame: Up to 23.0 months
Population: Subset of the Full Analysis Set includes all participants who received any amount of study drug and had a confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Run-In 0.9 mg/kg 3Q4W | Time to Response (TTR) (Part B) | 1.4 Months |