Advanced Solid Tumors, Lymphoma
Conditions
Keywords
Advanced Solid Tumors, E7766, Intratumoral Injection, Stimulator of Interferon Genes Agonist, Interferons, Antineoplastic Agents, Lymphoma, Melanoma, Breast Cancer, Colorectal Cancer, Squamous Cell Carcinoma of the Head and Neck, Oesophageal Squamous Cell Carcinoma, Adenocarcinoma of the Gastroesophageal Junction or Gastric
Brief summary
This is an open label, multicenter, phase 1/1b study to assess safety/tolerability and preliminary clinical activity of E7766 as a single agent administered intratumorally in participants with advanced solid tumors or lymphomas.
Detailed description
The Phase 1/1b study consist of two parts: Dose Escalation and Dose Expansion. In the Dose Escalation Part, E7766 will be administered intratumorally in participants with advanced solid tumors or lymphomas to assess safety/tolerability profile of E7766 and to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of E7766. In the Dose Expansion Part, E7766 at RP2D will be administered to participants with melanoma, head and neck squamous cell carcinoma (HNSCC), breast cancer, colorectal cancer, and/or other tumors including lymphomas to confirm safety and assess preliminary clinical activity of E7766 as a single agent. Clinical activity will be evaluated by objective response rate (ORR), duration of response (DOR), and disease control rate (DCR) on treatment with E7766.
Interventions
DRUGE7766
E7766, solution, intratumorally
Sponsors
H3 Biomedicine Inc.
Eisai Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Participants with solid tumors or lymphomas, confirmed by available histopathology records or current biopsy, that are advanced, nonresectable, or recurrent and progressing since last antitumor therapy, and for which no alternative standard therapy exists. 2. Participants must have a minimum of one injectable lesion which is also accessible for biopsy, and if available, one other measurable lesion also accessible for biopsy. An injectable lesion is defined as being measurable (defined below) with a maximum of 3.0 centimeter (cm) longest diameter, accessible for injection as judged by the investigator, and has not been subjected to any prior intratumoral treatment or radiotherapy. Lesions selected for injection must not be too close to a major vessel and not be associated with increased risk of bleeding, example, subcapsular liver lesions or hypervascular tumors. Measurable lesions are: 1. Solid tumors: At least 1 lesion of greater than or equal to (\>=1) cm by longest axial diameter or \>=1.5 cm short axis diameter if a nodal lesion, which is serially measurable according to modified Response evaluation criteria in solid tumors (RECIST) 1.1 using CT/MRI or photography. Lesions that have had external beam radiotherapy or locoregional therapies such as radiofrequency (RF) ablation must show evidence of progression to be deemed a target lesion. 2. Lymphoma: At least 1 lymph node with a longest diameter greater than (\>)1.5 cm or an extranodal lesion with a longest diameter \>1.0 cm 3. Participants with prior Hepatitis B or C are eligible if they have adequate liver function 4. Adequate bone marrow function: 1. Absolute neutrophil count (ANC) \>=1000 per cubic millimeter (/mm\^3) (\>=1.0\*10\^3 per microliter \[/mcL\]) 2. Platelets \>=75,000/mm\^3 (\>=75\*10\^ 9 per liter \[/L\]) 3. Hemoglobin \>=9.0 grams per deciliter (g/dL) 5. Adequate liver function defined by: 1. Adequate blood coagulation function as evidenced by an International Normalized Ratio (INR) less than or equal to (\<=)1.5 2. Total bilirubin \<=1.5\*upper limit of the normal range (ULN) except for unconjugated hyperbilirubinemia or Gilbert's syndrome 3. Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) \<=3\*ULN (in the case of liver metastasis \<=5\*ULN) unless there are bone metastases. Participants with ALP values \>3\*ULN and known to have bone metastases can be included.
Exclusion criteria
1. Other malignancy active within the previous 2 years except for basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast that has completed curative therapy. 2. Known human immunodeficiency virus (HIV) infection. 3. Major surgery within 4 weeks before the first dose of study drug. 4. Brain metastases that are untreated or in the posterior fossa or involve the meninges. Participants with stable or progressing brain metastases (except in the posterior fossa or involving the meninges) previously treated with brain stereotactic radiotherapy (SRT), whole-brain radiotherapy (WBRT) and/or surgery are allowed as long as the participant is asymptomatic neurologically and does not require immediate local intervention (radiotherapy and/or surgery). In addition, participants must be off immunosuppressive doses of systemic steroids (\>10 milligram per day (mg/d) prednisone or equivalent) for at least 4 weeks before study drug administration. 5. Prolongation of corrected QT (QTc) interval to \>450 millisecond (msec) for males and females when electrolytes balance is normal. 6. Females who are breastfeeding or pregnant at screening or baseline (as documented by a positive beta-human chorionic gonadotropin \[ß-hCG\] (or human chorionic gonadotropin \[hCG\]) test with a minimum sensitivity of 25 units per liter (IU/L) or equivalent units of ß-hCG \[or hCG\]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug. 7. Females of childbearing potential must not have had unprotected sexual intercourse within 30 days before study entry and must agree to use a highly effective method of contraception (total abstinence \[if it is their preferred and usual lifestyle\], a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 180 days after study drug discontinuation. For sites outside of the European Union, it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the participant, then the participant must agree to use a medically acceptable method of contraception, that is, double barrier methods of contraception such as condom plus diaphragm or cervical/vault cap with spermicide. If currently abstinent, the participant must agree to use a highly effective method as described above if she becomes sexually active during the study period or for 180 days after study drug discontinuation. Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 28 days before dosing and must continue to use the same contraceptive during the study and for 180 days after study drug discontinuation. 8. Male participants who are partners of women of childbearing potential must use a condom and spermicide and their female partners if of childbearing potential must use a highly effective method of contraception beginning at least 1 menstrual cycle prior to starting study drug(s), throughout the entire study period, and for 180 days after the last dose of study drug, unless the male participants are totally sexually abstinent or have undergone a successful vasectomy with confirmed azoospermia or unless the female partners have been sterilized surgically or are otherwise proven sterile. No sperm donation is allowed during the study period or for 180 days after study drug discontinuation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Escalation Part: Number of Participants With Dose-limiting Toxicities (DLTs) | Cycle 1 (Cycle length= 21 days) | DLTs were predefined as any of the following toxicities occurring during Cycle 1 and were assessed by the investigator according to National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] version (v) 5.0. as related to E7766. Nonhematologic toxicity greater than or equal to (\>=) Grade 3 (NCI CTCAE v. 5.0), except Grade 3 fatigue less than (\<) 5 days. Asymptomatic Grade 3 or 4 laboratory abnormalities that were corrected within 72 hours. \>=Grade 3 nausea, vomiting, and diarrhea unless lasting greater than (\>) 48 hours despite optimal supportive care. Hematologic toxicity: Grade 4 neutropenia for \>=5 days, or febrile neutropenia. Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with hemorrhage. A DLT may have continued treatment at a reduced dose if the DLT had resolved and in the opinion of the investigator the participant was benefiting from treatment. In case of recurrence of the DLT at a lower dose, E7766 treatment was discontinued. |
| Number of Participants With Any Treatment-emergent Adverse Events (TEAEs) | From the first dose of the study drug up to 90 days after the last dose (up to 9 months and 14 days) | A TEAE was defined as an adverse event (AE) that emerges during treatment (on or after the first dose of study drug up to 90 days after the participant's last dose) or start day of another anticancer therapy, whichever is earlier; or in case participant has initiated new anticancer therapy within 30 days, then AEs occurring for 30 days following the last dose of E7766, having been absent at pretreatment (Baseline) or reemerges during treatment, having been present at pretreatment (Baseline) but stopped before treatment, or worsens in severity during treatment relative to the pretreatment state, when the AE is continuous. |
| Dose Expansion Part: Objective Response Rate Based on Modified Response Evaluation Criteria In Solid Tumors (mRECIST) v1.1 | From date of first dose of study drug until confirmed CR or PR (up to 29 months) | ORR was defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) for target and non-target lesions. CR was defined as the disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in the short axis to less than 10 millimeter (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. The tumor assessment was done using number of lesions based on modified RECIST 1.1 as per investigator assessment for assessing tumor burden up to 10 target lesions with up to 5 target lesions per organ. |
| Dose Expansion Part: ORR Based on Immune Response Evaluation Criteria in Solid Tumors (iRECIST) | From date of first dose of study drug until confirmed iCR or iPR (up to 29 months) | ORR was defined as the percentage of participants whose BOR was iCR or iPR according to iRECIST as per investigator assessment. iCR: immune complete response achieved with disappearance of all target lesions iCPD: immune confirmed progressive disease when there is either 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions iSD: immune stable disease in the absence of iCR or iPD. iUPD: immune unconfirmed progressive disease when iPD is unconfirmed NE: not evaluable. |
| Dose Expansion Part: Duration of Response (DOR) Based on mRECIST v1.1 | From first documented confirmed CR or PR until first documentation of PD or death (up to 29 months) | DOR was defined as time from the first documented of CR or PR to the date of first documentation of PD based on modified RECIST 1.1 as per investigator assessment or death (whichever occurs first). CR was defined as the disappearance of all target lesions and non-target lesions. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. PD for target lesion, was defined as a minimum 20% increase and a minimum 5 mm absolute increase in sum of diameters compared to nadir, or PD for non-target lesion(s) or unequivocal new lesion(s). Nadir was defined as lowest measure sum of diameters of target lesions at any time point from baseline onward. The tumor assessment was done using number of lesions based on modified RECIST 1.1 for assessing tumor burden up to 10 target lesions with up to 5 target lesions per organ. |
| Dose Expansion Part: DOR Based on iRECIST | From first documented confirmed iCR or iPR until first documentation of iPD or death (up to 29 months) | DOR: time from date of first observation of response (iPR or iCR) to date of the first observation of progression based on iRECIST 1.1 as per investigator assessment, or date of death, whatever the cause. iCR: immune complete response achieved with disappearance of all target lesions iCPD: immune confirmed progressive disease when there is either 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Dose Expansion Part: Disease Control Rate (DCR) Based on mRECIST v1.1 | From first dose of study drug until confirmed CR or PR or >=5 weeks after first dose for SD (up to 29 months) | DCR was defined as the percentage of participants with a best overall response of CR or PR, or stable disease (SD) based on mRECIST 1.1 as per investigator assessment. Best overall response of SD must have been \>=5 weeks after randomization. CR was defined as disappearance of any intratumoral arterial enhancement in all target lesions. PR was defined as at least a 30% decrease in the sum of diameters of viable (enhancement of arterial phase) target lesions taking as reference the baseline sum of the diameters of target lesions. SD was when a case does not qualify for either PR or PD and was new non-target lesions. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the baseline sum of diameters of target lesions. |
| Dose Expansion Part: DCR Based on iRECIST | From first dose of study drug until confirmed iCR or iPR or >=5 weeks after first dose for iSD (up to 29 months) | DCR: percentage of participants with a confirmed iCR, iPR, or i-SD (duration of iSD \>=5 weeks). DCR was assessed on iRECIST v1.1 as per investigator assessment. iCR: immune complete response achieved with disappearance of all target lesions iCPD: immune confirmed progressive disease when there is either 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions iSD: immune stable disease in the absence of iCR or iPD. iUPD: immune unconfirmed progressive disease when iPD is unconfirmed NE: not evaluable. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for E7766 | Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose; Dose Expansion: Cycle 1 Days 1 and 15: predose up to 2 hours postdose (Cycle length=21 days) | Tmax was quantified using validated liquid LC-MS/MS methods. |
| Part: AUC(0-t): Area Under the Plasma Concentration From Time Zero to Last Curve for E7766 | Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose; Dose Expansion: Cycle 1 Days 1 and 15: predose up to 2 hours postdose (Cycle length=21 days) | AUC was quantified using validated liquid LC-MS/MS methods. |
| AUC(0-inf): Area Under the Plasma Concentration From Time Zero to Infinity Curve for E7766 | Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose; Dose Expansion: Cycle 1 Days 1 and 15: predose up to 2 hours postdose (Cycle length=21 days) | AUC(0-inf) was quantified using liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. |
| t1/2: Terminal Elimination Half-life for E7766 | Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose; Dose Expansion: Cycle 1 Days 1 and 15: predose up to 2 hours postdose (Cycle length=21 days) | t1/2 was quantified using validated liquid LC-MS/MS methods. |
| Dose Escalation Part: CL/F: Apparent Total Body Clearance for E7766 | Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length=21 days) | CL/F was quantified using validated liquid LC-MS/MS methods. |
| Dose Escalation Part: Vd/F: Apparent Volume of Distribution for E7766 | Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length=21 days) | Vd/F was quantified using validated liquid LC-MS/MS methods. |
| Dose Escalation Part: CLr: Renal Clearance for E7766 | Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length=21 days) | CLr was quantified using validated liquid LC-MS/MS methods. |
| Dose Escalation Part: Rac (Cmax): Accumulation Ratio Based on Cmax for E7766 | Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length=21 days) | Rac (Cmax) was calculated as the ratio of Cmax on Cycle 1 Day 15 divided by Cmax on Cycle 1 Day 1. Accumulation ratio was quantified using validated liquid LC-MS/MS methods. |
| Dose Escalation Part: Percentage (Fraction) Excreted (fe) in Urine for E7766 | Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length=21 days) | fe was defined as fraction of administered drug (E7766) excreted/recovered in urine. fe was quantified using validated liquid LC-MS/MS methods. |
| Dose Escalation Part: Percentage (Fraction) Excreted (fe) in Feces for E7766 | Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length=21 days) | fe was defined as fraction of administered drug (E7766) excreted/recovered in feces. fe was quantified using validated liquid LC-MS/MS methods. |
| Progression Free Survival (PFS) Based on mRECIST v1.1 | From first dose of study drug until confirmed PD or death up to 6 months 18 days (Dose Escalation Part) and up to 29 months (Dose Expansion Part) | PFS was defined as the time from the first study dose date to the date of first documentation of disease progression or death (whichever occurred first) based on mRECIST v1.1 as per investigator assessment. PD was defined as at least a 20% increase in the sum of LD of target and non-target lesions as compared with the smallest sum of LD and the increase of LD was at least 5 mm (including new lesions). |
| PFS Based on iRECIST | From first dose of study drug until confirmed PD or death up to 6 months 18 days (Dose Escalation Part) and up to 29 months (Dose Expansion Part) | PFS was defined as the time from the first dose date to the date of iPD or date of death (whichever occurred first) according to iRECIST version 1.1 as per investigator assessment. iCPD: immune confirmed progressive disease when there is either 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Overall Survival (OS) | From first dose of study drug until confirmed PD or death up to 6 months 18 days (Dose Escalation Part) and up to 29 months (Dose Expansion Part) | OS was measured from the date of first dose of study drug until date of death from any cause. OS event was defined as deaths no later than data cut off date or date of death of a participant. |
| Percent Change From Baseline in Tumor Size | Baseline to up to 6 months and 18 days (Dose Escalation Part) and up to 29 months (Dose Expansion Part) | Percent change from baseline in tumor size was calculated for the first injected lesion based on Investigator Assessment. |
| Dose Escalation Part: Rac (AUC0-t): Accumulation Ratio Based on AUC for E7766 | Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length=21 days) | Rac (AUC0-t) was calculated as the ratio of AUC(0-t) on Cycle 1 Day 15 divided by AUC(0-t) on Cycle 1 Day 1. Accumulation ratio was quantified using validated liquid LC-MS/MS methods. |
| Dose Escalation Part: ORR Based on iRECIST | From date of first dose of study drug until confirmed iCR or iPR (up to 6 months and 18 days) | ORR was defined as the percentage of participants whose BOR was iCR or iPR according to iRECIST as per investigator assessment. iCR: immune complete response achieved with disappearance of all target lesions iCPD: immune confirmed progressive disease when there is either 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions iSD: immune stable disease in the absence of iCR or iPD iUPD: immune unconfirmed progressive disease when iPD is unconfirmed NE: not evaluable. |
| Dose Escalation Part: ORR Based on mRECIST v1.1 | From date of first dose of study drug until confirmed CR or PR (up to 6 months and 18 days) | ORR was defined as the percentage of participants with a BOR of CR or PR for target and non-target lesions. CR was defined as the disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in the short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. The tumor assessment was done using number of lesions based on modified RECIST 1.1 as per investigator assessment for assessing tumor burden up to 10 target lesions with up to 5 target lesions per organ. |
| Dose Escalation Part: DOR Based on iRECIST | From first documented confirmed iCR or iPR until first documentation of iPD or death (up to 6 months and 18 days) | DOR: time from date of first observation of response (iPR or iCR) to date of the first observation of progression based on iRECIST 1.1 as per investigator assessment, or date of death, whatever the cause. iCR: immune complete response achieved with disappearance of all target lesions iCPD: immune confirmed progressive disease when there is either 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Dose Escalation Part: DOR Based on mRECIST v1.1 | From first documented confirmed CR or PR until first documentation of PD or death (up to 6 months and 18 days) | DOR was defined as time from the first documented of CR or PR to the date of first documentation of PD based on modified RECIST 1.1as per investigator assessment or death (whichever occurs first). CR was defined as the disappearance of all target lesions and non-target lesions. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. PD for target lesion, was defined as a minimum 20% increase and a minimum 5 mm absolute increase in sum of diameters compared to nadir, or PD for non-target lesion(s) or unequivocal new lesion(s). Nadir was defined as lowest measure sum of diameters of target lesions at any time point from baseline onward. The tumor assessment was done using number of lesions based on modified RECIST 1.1 for assessing tumor burden up to 10 target lesions with up to 5 target lesions per organ. |
| Dose Escalation Part: DCR Based on iRECIST | From first dose of study drug until confirmed iCR or iPR or >=5 weeks after first dose for iSD (up to 6 months and 18 days) | DCR: percentage of participants with a confirmed iCR, iPR, or i-SD (duration of iSD \>=5 weeks). DCR was assessed on iRECIST v1.1 as per investigator assessment. iCR: immune complete response achieved with disappearance of all target lesions iCPD: immune confirmed progressive disease when there is either 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions iSD: immune stable disease in the absence of iCR or iPD iUPD: immune unconfirmed progressive disease when iPD is unconfirmed NE: not evaluable. |
| Dose Escalation Part: DCR Based on mRECIST v1.1 | From first dose of study drug until confirmed CR or PR or >=5 weeks after first dose for SD (up to 6 months and 18 days) | DCR was defined as the percentage of participants with a best overall response of CR or PR, or SD based on mRECIST 1.1 as per investigator assessment. Best overall response of SD must have been \>=7 weeks after randomization. CR was defined as disappearance of any intratumoral arterial enhancement in all target lesions. PR was defined as at least a 30% decrease in the sum of diameters of viable (enhancement of arterial phase) target lesions taking as reference the baseline sum of the diameters of target lesions. SD was when a case does not qualify for either PR or PD and was new non-target lesions. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the baseline sum of diameters of target lesions. |
| Cmax: Maximum Observed Plasma Concentration for E7766 | Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose; Dose Expansion: Cycle 1 Days 1 and 15: predose up to 2 hours postdose (Cycle length=21 days) | Cmax was quantified using liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. |
Countries
France, South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 8 investigative sites in the United States, France, and United Kingdom from 24 February 2020 to 26 July 2022.
Pre-assignment details
A total of 31 participants were screened, of which 7 were screen failures and 24 were enrolled to receive study treatment in the Dose Escalation Part of this study. The study was terminated due to sponsor's strategic decision, which is unrelated to safety, therefore no participants were enrolled in the Dose Expansion part. Hence, no data collection and analysis were done during Dose Expansion part of this study.
Participants by arm
| Arm | Count |
|---|---|
| Dose Escalation Part: E7766 75 mcg Participants received E7766 75 mcg, injection, intratumorally on Days 1, 8, and 15 in the first cycle of 21 days and then on Day 1 of each subsequent 21-days cycle, once every 3 weeks until PD or until other discontinuation criteria whichever occurred first. | 2 |
| Dose Escalation Part: E7766 150 mcg Participants received E7766 150 mcg injection, intratumorally on Days 1, 8, and 15 in the first cycle of 21 days and then on Day 1 of each subsequent 21-days cycle, once every 3 weeks until PD or until other discontinuation criteria whichever occurred first. | 2 |
| Dose Escalation Part: E7766 300 mcg Participants received E7766 300 mcg injection, intratumorally on Days 1, 8, and 15 in the first cycle of 21 days and then on Day 1 of each subsequent 21-days cycle, once every 3 weeks until PD or until other discontinuation criteria whichever occurred first. | 2 |
| Dose Escalation Part: E7766 600 mcg Participants received E7766 600 mcg injection, intratumorally on Days 1, 8, and 15 in the first cycle of 21 days and then on Day 1 of each subsequent 21-days cycle, once every 3 weeks until PD or until other discontinuation criteria whichever occurred first. | 11 |
| Dose Escalation Part: E7766 780 mcg Participants received E7766 780 mcg injection, intratumorally on Days 1, 8, and 15 in the first cycle of 21 days and then on Day 1 of each subsequent 21-days cycle, once every 3 weeks until PD or until other discontinuation criteria whichever occurred first. | 6 |
| Dose Escalation Part: E7766 1000 mcg Participants received E7766 1000 mcg injection, intratumorally on Days 1, 8, and 15 in the first cycle of 21 days and then on Day 1 of each subsequent 21-days cycle, once every 3 weeks until PD or until other discontinuation criteria whichever occurred first. | 1 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Other | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Dose Escalation Part: E7766 75 mcg | Dose Escalation Part: E7766 150 mcg | Dose Escalation Part: E7766 300 mcg | Dose Escalation Part: E7766 600 mcg | Dose Escalation Part: E7766 780 mcg | Dose Escalation Part: E7766 1000 mcg | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 72.0 years STANDARD_DEVIATION 4.24 | 53.5 years STANDARD_DEVIATION 13.44 | 49.5 years STANDARD_DEVIATION 12.02 | 57.4 years STANDARD_DEVIATION 12.95 | 60.5 years STANDARD_DEVIATION 17.39 | 61.0 years | 58.5 years STANDARD_DEVIATION 13.44 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 2 Participants | 2 Participants | 10 Participants | 5 Participants | 1 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 2 Participants | 2 Participants | 10 Participants | 6 Participants | 1 Participants | 23 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 1 Participants | 4 Participants | 3 Participants | 0 Participants | 10 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 1 Participants | 7 Participants | 3 Participants | 1 Participants | 14 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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 2 | 1 / 2 | 1 / 2 | 4 / 11 | 5 / 6 | 1 / 1 |
| other Total, other adverse events | 2 / 2 | 2 / 2 | 2 / 2 | 11 / 11 | 6 / 6 | 1 / 1 |
| serious Total, serious adverse events | 0 / 2 | 0 / 2 | 1 / 2 | 3 / 11 | 3 / 6 | 1 / 1 |
Outcome results
Primary
Dose Escalation Part: Number of Participants With Dose-limiting Toxicities (DLTs)
DLTs were predefined as any of the following toxicities occurring during Cycle 1 and were assessed by the investigator according to National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] version (v) 5.0. as related to E7766. Nonhematologic toxicity greater than or equal to (\>=) Grade 3 (NCI CTCAE v. 5.0), except Grade 3 fatigue less than (\<) 5 days. Asymptomatic Grade 3 or 4 laboratory abnormalities that were corrected within 72 hours. \>=Grade 3 nausea, vomiting, and diarrhea unless lasting greater than (\>) 48 hours despite optimal supportive care. Hematologic toxicity: Grade 4 neutropenia for \>=5 days, or febrile neutropenia. Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with hemorrhage. A DLT may have continued treatment at a reduced dose if the DLT had resolved and in the opinion of the investigator the participant was benefiting from treatment. In case of recurrence of the DLT at a lower dose, E7766 treatment was discontinued.
Time frame: Cycle 1 (Cycle length= 21 days)
Population: The DLT analysis set included all participants in the Dose Escalation part who completed Cycle 1 without incurring certain major protocol deviations (for instance those related to dosing or others identified before database lock) with at least 2 E7766 injections during Cycle 1 and were evaluable for DLT, or participants who experienced DLT during Cycle 1.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation Part: E7766 75 mcg | Dose Escalation Part: Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
| Dose Escalation Part: E7766 150 mcg | Dose Escalation Part: Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
| Dose Escalation Part: E7766 300 mcg | Dose Escalation Part: Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
| Dose Escalation Part: E7766 600 mcg | Dose Escalation Part: Number of Participants With Dose-limiting Toxicities (DLTs) | 2 Participants |
| Dose Escalation Part: E7766 780 mcg | Dose Escalation Part: Number of Participants With Dose-limiting Toxicities (DLTs) | 1 Participants |
Primary
Dose Expansion Part: DCR Based on iRECIST
DCR: percentage of participants with a confirmed iCR, iPR, or i-SD (duration of iSD \>=5 weeks). DCR was assessed on iRECIST v1.1 as per investigator assessment. iCR: immune complete response achieved with disappearance of all target lesions iCPD: immune confirmed progressive disease when there is either 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions iSD: immune stable disease in the absence of iCR or iPD. iUPD: immune unconfirmed progressive disease when iPD is unconfirmed NE: not evaluable.
Time frame: From first dose of study drug until confirmed iCR or iPR or >=5 weeks after first dose for iSD (up to 29 months)
Population: The full analysis set included all participants who received at least 1 dose of study drug. No participants were enrolled in the Dose Expansion part. Hence, no data collection and analysis were done during Dose Expansion part.
Primary
Dose Expansion Part: Disease Control Rate (DCR) Based on mRECIST v1.1
DCR was defined as the percentage of participants with a best overall response of CR or PR, or stable disease (SD) based on mRECIST 1.1 as per investigator assessment. Best overall response of SD must have been \>=5 weeks after randomization. CR was defined as disappearance of any intratumoral arterial enhancement in all target lesions. PR was defined as at least a 30% decrease in the sum of diameters of viable (enhancement of arterial phase) target lesions taking as reference the baseline sum of the diameters of target lesions. SD was when a case does not qualify for either PR or PD and was new non-target lesions. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the baseline sum of diameters of target lesions.
Time frame: From first dose of study drug until confirmed CR or PR or >=5 weeks after first dose for SD (up to 29 months)
Population: The full analysis set included all participants who received at least 1 dose of study drug. No participants were enrolled in the Dose Expansion part. Hence, no data collection and analysis were done during Dose Expansion part.
Primary
Dose Expansion Part: DOR Based on iRECIST
DOR: time from date of first observation of response (iPR or iCR) to date of the first observation of progression based on iRECIST 1.1 as per investigator assessment, or date of death, whatever the cause. iCR: immune complete response achieved with disappearance of all target lesions iCPD: immune confirmed progressive disease when there is either 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: From first documented confirmed iCR or iPR until first documentation of iPD or death (up to 29 months)
Population: The full analysis set included all participants who received at least 1 dose of study drug. No participants were enrolled in the Dose Expansion part. Hence, no data collection and analysis were done during Dose Expansion part.
Primary
Dose Expansion Part: Duration of Response (DOR) Based on mRECIST v1.1
DOR was defined as time from the first documented of CR or PR to the date of first documentation of PD based on modified RECIST 1.1 as per investigator assessment or death (whichever occurs first). CR was defined as the disappearance of all target lesions and non-target lesions. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. PD for target lesion, was defined as a minimum 20% increase and a minimum 5 mm absolute increase in sum of diameters compared to nadir, or PD for non-target lesion(s) or unequivocal new lesion(s). Nadir was defined as lowest measure sum of diameters of target lesions at any time point from baseline onward. The tumor assessment was done using number of lesions based on modified RECIST 1.1 for assessing tumor burden up to 10 target lesions with up to 5 target lesions per organ.
Time frame: From first documented confirmed CR or PR until first documentation of PD or death (up to 29 months)
Population: The full analysis set included all participants who received at least 1 dose of study drug. No participants were enrolled in the Dose Expansion part. Hence, no data collection and analysis were done during Dose Expansion part.
Primary
Dose Expansion Part: Objective Response Rate Based on Modified Response Evaluation Criteria In Solid Tumors (mRECIST) v1.1
ORR was defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) for target and non-target lesions. CR was defined as the disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in the short axis to less than 10 millimeter (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. The tumor assessment was done using number of lesions based on modified RECIST 1.1 as per investigator assessment for assessing tumor burden up to 10 target lesions with up to 5 target lesions per organ.
Time frame: From date of first dose of study drug until confirmed CR or PR (up to 29 months)
Population: The full analysis set included all participants who received at least 1 dose of study drug. No participants were enrolled in the Dose Expansion part. Hence, no data collection and analysis were done during Dose Expansion part.
Primary
Dose Expansion Part: ORR Based on Immune Response Evaluation Criteria in Solid Tumors (iRECIST)
ORR was defined as the percentage of participants whose BOR was iCR or iPR according to iRECIST as per investigator assessment. iCR: immune complete response achieved with disappearance of all target lesions iCPD: immune confirmed progressive disease when there is either 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions iSD: immune stable disease in the absence of iCR or iPD. iUPD: immune unconfirmed progressive disease when iPD is unconfirmed NE: not evaluable.
Time frame: From date of first dose of study drug until confirmed iCR or iPR (up to 29 months)
Population: The full analysis set included all participants who received at least 1 dose of study drug. No participants were enrolled in the Dose Expansion part. Hence, no data collection and analysis were done during Dose Expansion part.
Primary
Number of Participants With Any Treatment-emergent Adverse Events (TEAEs)
A TEAE was defined as an adverse event (AE) that emerges during treatment (on or after the first dose of study drug up to 90 days after the participant's last dose) or start day of another anticancer therapy, whichever is earlier; or in case participant has initiated new anticancer therapy within 30 days, then AEs occurring for 30 days following the last dose of E7766, having been absent at pretreatment (Baseline) or reemerges during treatment, having been present at pretreatment (Baseline) but stopped before treatment, or worsens in severity during treatment relative to the pretreatment state, when the AE is continuous.
Time frame: From the first dose of the study drug up to 90 days after the last dose (up to 9 months and 14 days)
Population: The safety analysis set included all participants who received at least 1 dose of study drug. No participants were enrolled in the Dose Expansion part. Hence, no data collection and analysis were done during Dose Expansion part.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation Part: E7766 75 mcg | Number of Participants With Any Treatment-emergent Adverse Events (TEAEs) | 2 Participants |
| Dose Escalation Part: E7766 150 mcg | Number of Participants With Any Treatment-emergent Adverse Events (TEAEs) | 2 Participants |
| Dose Escalation Part: E7766 300 mcg | Number of Participants With Any Treatment-emergent Adverse Events (TEAEs) | 2 Participants |
| Dose Escalation Part: E7766 600 mcg | Number of Participants With Any Treatment-emergent Adverse Events (TEAEs) | 11 Participants |
| Dose Escalation Part: E7766 780 mcg | Number of Participants With Any Treatment-emergent Adverse Events (TEAEs) | 6 Participants |
| Dose Escalation Part: E7766 1000 mcg | Number of Participants With Any Treatment-emergent Adverse Events (TEAEs) | 1 Participants |
Secondary
AUC(0-inf): Area Under the Plasma Concentration From Time Zero to Infinity Curve for E7766
AUC(0-inf) was quantified using liquid chromatography tandem mass spectrometry (LC-MS/MS) methods.
Time frame: Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose; Dose Expansion: Cycle 1 Days 1 and 15: predose up to 2 hours postdose (Cycle length=21 days)
Population: The PK analysis set included the group of participants who have received at least 1 dose of study drug and have at least 1 evaluable plasma concentration. No participants were enrolled in the Dose Expansion part. Hence, no data collection and analysis were done during Dose Expansion part. Here overall number analyzed N were the participants who were evaluable for the outcome measure and number analyzed n are the participants who were evaluable for given timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Part: E7766 150 mcg | AUC(0-inf): Area Under the Plasma Concentration From Time Zero to Infinity Curve for E7766 | Cycle 1 Day 1 | 5.58 h*ng/mL | — |
| Dose Escalation Part: E7766 150 mcg | AUC(0-inf): Area Under the Plasma Concentration From Time Zero to Infinity Curve for E7766 | Cycle 1 Day 15 | 2.18 h*ng/mL | Geometric Coefficient of Variation 35.4 |
| Dose Escalation Part: E7766 300 mcg | AUC(0-inf): Area Under the Plasma Concentration From Time Zero to Infinity Curve for E7766 | Cycle 1 Day 15 | 5.79 h*ng/mL | — |
| Dose Escalation Part: E7766 300 mcg | AUC(0-inf): Area Under the Plasma Concentration From Time Zero to Infinity Curve for E7766 | Cycle 1 Day 1 | 4.64 h*ng/mL | Geometric Coefficient of Variation 25.1 |
| Dose Escalation Part: E7766 600 mcg | AUC(0-inf): Area Under the Plasma Concentration From Time Zero to Infinity Curve for E7766 | Cycle 1 Day 15 | 5.16 h*ng/mL | Geometric Coefficient of Variation 83.6 |
| Dose Escalation Part: E7766 600 mcg | AUC(0-inf): Area Under the Plasma Concentration From Time Zero to Infinity Curve for E7766 | Cycle 1 Day 1 | 8.07 h*ng/mL | Geometric Coefficient of Variation 38.5 |
| Dose Escalation Part: E7766 780 mcg | AUC(0-inf): Area Under the Plasma Concentration From Time Zero to Infinity Curve for E7766 | Cycle 1 Day 15 | 7.07 h*ng/mL | Geometric Coefficient of Variation 75.7 |
| Dose Escalation Part: E7766 780 mcg | AUC(0-inf): Area Under the Plasma Concentration From Time Zero to Infinity Curve for E7766 | Cycle 1 Day 1 | 8.93 h*ng/mL | Geometric Coefficient of Variation 54.9 |
| Dose Escalation Part: E7766 1000 mcg | AUC(0-inf): Area Under the Plasma Concentration From Time Zero to Infinity Curve for E7766 | Cycle 1 Day 1 | 10.4 h*ng/mL | — |
Secondary
Cmax: Maximum Observed Plasma Concentration for E7766
Cmax was quantified using liquid chromatography tandem mass spectrometry (LC-MS/MS) methods.
Time frame: Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose; Dose Expansion: Cycle 1 Days 1 and 15: predose up to 2 hours postdose (Cycle length=21 days)
Population: The Pharmacokinetic (PK) analysis set included the group of participants who have received at least 1 dose of study drug and have at least 1 evaluable plasma concentration. No participants were enrolled in the Dose Expansion part. Hence, no data collection and analysis were done during Dose Expansion part. Here number analyzed n are the participants who were evaluable for this outcome measure for given timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Part: E7766 75 mcg | Cmax: Maximum Observed Plasma Concentration for E7766 | Cycle 1 Day 1 | 4.23 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 87.4 |
| Dose Escalation Part: E7766 75 mcg | Cmax: Maximum Observed Plasma Concentration for E7766 | Cycle 1 Day 15 | 1.29 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 22.7 |
| Dose Escalation Part: E7766 150 mcg | Cmax: Maximum Observed Plasma Concentration for E7766 | Cycle 1 Day 15 | 2.23 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 58.1 |
| Dose Escalation Part: E7766 150 mcg | Cmax: Maximum Observed Plasma Concentration for E7766 | Cycle 1 Day 1 | 2.77 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 7.16 |
| Dose Escalation Part: E7766 300 mcg | Cmax: Maximum Observed Plasma Concentration for E7766 | Cycle 1 Day 15 | 4.53 nanogram per milliliter (ng/mL) | — |
| Dose Escalation Part: E7766 300 mcg | Cmax: Maximum Observed Plasma Concentration for E7766 | Cycle 1 Day 1 | 2.95 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 9.85 |
| Dose Escalation Part: E7766 600 mcg | Cmax: Maximum Observed Plasma Concentration for E7766 | Cycle 1 Day 15 | 2.72 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 168 |
| Dose Escalation Part: E7766 600 mcg | Cmax: Maximum Observed Plasma Concentration for E7766 | Cycle 1 Day 1 | 8.03 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 95.8 |
| Dose Escalation Part: E7766 780 mcg | Cmax: Maximum Observed Plasma Concentration for E7766 | Cycle 1 Day 15 | 9.33 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 34.8 |
| Dose Escalation Part: E7766 780 mcg | Cmax: Maximum Observed Plasma Concentration for E7766 | Cycle 1 Day 1 | 11.3 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 30.6 |
| Dose Escalation Part: E7766 1000 mcg | Cmax: Maximum Observed Plasma Concentration for E7766 | Cycle 1 Day 1 | 9.99 nanogram per milliliter (ng/mL) | — |
Secondary
Dose Escalation Part: CL/F: Apparent Total Body Clearance for E7766
CL/F was quantified using validated liquid LC-MS/MS methods.
Time frame: Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length=21 days)
Population: The PK analysis set included the group of participants who have received at least 1 dose of study drug and have at least 1 evaluable plasma concentration. As planned, this outcome measure was assessed in dose escalation part only. Here overall number analyzed N were the participants who were evaluable for the outcome measure and number analyzed n are the participants who were evaluable for given timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Part: E7766 150 mcg | Dose Escalation Part: CL/F: Apparent Total Body Clearance for E7766 | Cycle 1 Day 1 | 26.9 liter per hour (L/h) | — |
| Dose Escalation Part: E7766 150 mcg | Dose Escalation Part: CL/F: Apparent Total Body Clearance for E7766 | Cycle 1 Day 15 | 68.7 liter per hour (L/h) | Geometric Coefficient of Variation 35.3 |
| Dose Escalation Part: E7766 300 mcg | Dose Escalation Part: CL/F: Apparent Total Body Clearance for E7766 | Cycle 1 Day 15 | 51.8 liter per hour (L/h) | — |
| Dose Escalation Part: E7766 300 mcg | Dose Escalation Part: CL/F: Apparent Total Body Clearance for E7766 | Cycle 1 Day 1 | 64.6 liter per hour (L/h) | Geometric Coefficient of Variation 25.2 |
| Dose Escalation Part: E7766 600 mcg | Dose Escalation Part: CL/F: Apparent Total Body Clearance for E7766 | Cycle 1 Day 15 | 116.0 liter per hour (L/h) | Geometric Coefficient of Variation 83.7 |
| Dose Escalation Part: E7766 600 mcg | Dose Escalation Part: CL/F: Apparent Total Body Clearance for E7766 | Cycle 1 Day 1 | 74.4 liter per hour (L/h) | Geometric Coefficient of Variation 38.5 |
| Dose Escalation Part: E7766 780 mcg | Dose Escalation Part: CL/F: Apparent Total Body Clearance for E7766 | Cycle 1 Day 15 | 110.0 liter per hour (L/h) | Geometric Coefficient of Variation 75.9 |
| Dose Escalation Part: E7766 780 mcg | Dose Escalation Part: CL/F: Apparent Total Body Clearance for E7766 | Cycle 1 Day 1 | 87.3 liter per hour (L/h) | Geometric Coefficient of Variation 54.8 |
| Dose Escalation Part: E7766 1000 mcg | Dose Escalation Part: CL/F: Apparent Total Body Clearance for E7766 | Cycle 1 Day 1 | 90.3 liter per hour (L/h) | — |
Secondary
Dose Escalation Part: CLr: Renal Clearance for E7766
CLr was quantified using validated liquid LC-MS/MS methods.
Time frame: Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length=21 days)
Population: The PK analysis set included the group of participants who have received at least 1 dose of study drug and have at least 1 evaluable plasma concentration. As planned, this outcome measure was assessed in dose escalation part only. Here overall number analyzed N were the participants who were evaluable for the outcome measure and number analyzed n are the participants who were evaluable for given timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Part: E7766 75 mcg | Dose Escalation Part: CLr: Renal Clearance for E7766 | Cycle 1 Day 1 | 0.0218 Liter per hour (L/h) | Geometric Coefficient of Variation 76.3 |
| Dose Escalation Part: E7766 75 mcg | Dose Escalation Part: CLr: Renal Clearance for E7766 | Cycle 1 Day 15 | 0.0287 Liter per hour (L/h) | Geometric Coefficient of Variation 617 |
| Dose Escalation Part: E7766 150 mcg | Dose Escalation Part: CLr: Renal Clearance for E7766 | Cycle 1 Day 15 | 0.243 Liter per hour (L/h) | — |
| Dose Escalation Part: E7766 150 mcg | Dose Escalation Part: CLr: Renal Clearance for E7766 | Cycle 1 Day 1 | 0.0119 Liter per hour (L/h) | — |
| Dose Escalation Part: E7766 300 mcg | Dose Escalation Part: CLr: Renal Clearance for E7766 | Cycle 1 Day 15 | 0.164 Liter per hour (L/h) | — |
| Dose Escalation Part: E7766 300 mcg | Dose Escalation Part: CLr: Renal Clearance for E7766 | Cycle 1 Day 1 | 0.0304 Liter per hour (L/h) | Geometric Coefficient of Variation 14 |
| Dose Escalation Part: E7766 600 mcg | Dose Escalation Part: CLr: Renal Clearance for E7766 | Cycle 1 Day 15 | 0.412 Liter per hour (L/h) | Geometric Coefficient of Variation 320 |
| Dose Escalation Part: E7766 600 mcg | Dose Escalation Part: CLr: Renal Clearance for E7766 | Cycle 1 Day 1 | 0.0727 Liter per hour (L/h) | Geometric Coefficient of Variation 1030 |
| Dose Escalation Part: E7766 780 mcg | Dose Escalation Part: CLr: Renal Clearance for E7766 | Cycle 1 Day 15 | 0.0742 Liter per hour (L/h) | Geometric Coefficient of Variation 72.9 |
| Dose Escalation Part: E7766 780 mcg | Dose Escalation Part: CLr: Renal Clearance for E7766 | Cycle 1 Day 1 | 0.0474 Liter per hour (L/h) | Geometric Coefficient of Variation 54.2 |
| Dose Escalation Part: E7766 1000 mcg | Dose Escalation Part: CLr: Renal Clearance for E7766 | Cycle 1 Day 1 | 0.0256 Liter per hour (L/h) | — |
Secondary
Dose Escalation Part: DCR Based on iRECIST
DCR: percentage of participants with a confirmed iCR, iPR, or i-SD (duration of iSD \>=5 weeks). DCR was assessed on iRECIST v1.1 as per investigator assessment. iCR: immune complete response achieved with disappearance of all target lesions iCPD: immune confirmed progressive disease when there is either 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions iSD: immune stable disease in the absence of iCR or iPD iUPD: immune unconfirmed progressive disease when iPD is unconfirmed NE: not evaluable.
Time frame: From first dose of study drug until confirmed iCR or iPR or >=5 weeks after first dose for iSD (up to 6 months and 18 days)
Population: The full analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Part: E7766 75 mcg | Dose Escalation Part: DCR Based on iRECIST | 100.0 percentage of participants |
| Dose Escalation Part: E7766 150 mcg | Dose Escalation Part: DCR Based on iRECIST | 0.0 percentage of participants |
| Dose Escalation Part: E7766 300 mcg | Dose Escalation Part: DCR Based on iRECIST | 50.0 percentage of participants |
| Dose Escalation Part: E7766 600 mcg | Dose Escalation Part: DCR Based on iRECIST | 36.4 percentage of participants |
| Dose Escalation Part: E7766 780 mcg | Dose Escalation Part: DCR Based on iRECIST | 16.7 percentage of participants |
| Dose Escalation Part: E7766 1000 mcg | Dose Escalation Part: DCR Based on iRECIST | 0.0 percentage of participants |
Secondary
Dose Escalation Part: DCR Based on mRECIST v1.1
DCR was defined as the percentage of participants with a best overall response of CR or PR, or SD based on mRECIST 1.1 as per investigator assessment. Best overall response of SD must have been \>=7 weeks after randomization. CR was defined as disappearance of any intratumoral arterial enhancement in all target lesions. PR was defined as at least a 30% decrease in the sum of diameters of viable (enhancement of arterial phase) target lesions taking as reference the baseline sum of the diameters of target lesions. SD was when a case does not qualify for either PR or PD and was new non-target lesions. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the baseline sum of diameters of target lesions.
Time frame: From first dose of study drug until confirmed CR or PR or >=5 weeks after first dose for SD (up to 6 months and 18 days)
Population: The full analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Part: E7766 75 mcg | Dose Escalation Part: DCR Based on mRECIST v1.1 | 100.0 percentage of participants |
| Dose Escalation Part: E7766 150 mcg | Dose Escalation Part: DCR Based on mRECIST v1.1 | 0.0 percentage of participants |
| Dose Escalation Part: E7766 300 mcg | Dose Escalation Part: DCR Based on mRECIST v1.1 | 50.0 percentage of participants |
| Dose Escalation Part: E7766 600 mcg | Dose Escalation Part: DCR Based on mRECIST v1.1 | 36.4 percentage of participants |
| Dose Escalation Part: E7766 780 mcg | Dose Escalation Part: DCR Based on mRECIST v1.1 | 16.7 percentage of participants |
| Dose Escalation Part: E7766 1000 mcg | Dose Escalation Part: DCR Based on mRECIST v1.1 | 0.0 percentage of participants |
Secondary
Dose Escalation Part: DOR Based on iRECIST
DOR: time from date of first observation of response (iPR or iCR) to date of the first observation of progression based on iRECIST 1.1 as per investigator assessment, or date of death, whatever the cause. iCR: immune complete response achieved with disappearance of all target lesions iCPD: immune confirmed progressive disease when there is either 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: From first documented confirmed iCR or iPR until first documentation of iPD or death (up to 6 months and 18 days)
Population: The full analysis set included all participants who received at least 1 dose of study drug. Here, Overall number of participants analyzed signifies participants who had overall response (OR) (CR or PR) as per Investigator Assessment.
Secondary
Dose Escalation Part: DOR Based on mRECIST v1.1
DOR was defined as time from the first documented of CR or PR to the date of first documentation of PD based on modified RECIST 1.1as per investigator assessment or death (whichever occurs first). CR was defined as the disappearance of all target lesions and non-target lesions. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. PD for target lesion, was defined as a minimum 20% increase and a minimum 5 mm absolute increase in sum of diameters compared to nadir, or PD for non-target lesion(s) or unequivocal new lesion(s). Nadir was defined as lowest measure sum of diameters of target lesions at any time point from baseline onward. The tumor assessment was done using number of lesions based on modified RECIST 1.1 for assessing tumor burden up to 10 target lesions with up to 5 target lesions per organ.
Time frame: From first documented confirmed CR or PR until first documentation of PD or death (up to 6 months and 18 days)
Population: The full analysis set included all participants who received at least 1 dose of study drug. Here, Overall number of participants analyzed signifies participants who had OR (CR or PR) as per Investigator Assessment.
Secondary
Dose Escalation Part: ORR Based on iRECIST
ORR was defined as the percentage of participants whose BOR was iCR or iPR according to iRECIST as per investigator assessment. iCR: immune complete response achieved with disappearance of all target lesions iCPD: immune confirmed progressive disease when there is either 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions iSD: immune stable disease in the absence of iCR or iPD iUPD: immune unconfirmed progressive disease when iPD is unconfirmed NE: not evaluable.
Time frame: From date of first dose of study drug until confirmed iCR or iPR (up to 6 months and 18 days)
Population: The full analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Part: E7766 75 mcg | Dose Escalation Part: ORR Based on iRECIST | 0 percentage of participants |
| Dose Escalation Part: E7766 150 mcg | Dose Escalation Part: ORR Based on iRECIST | 0 percentage of participants |
| Dose Escalation Part: E7766 300 mcg | Dose Escalation Part: ORR Based on iRECIST | 0 percentage of participants |
| Dose Escalation Part: E7766 600 mcg | Dose Escalation Part: ORR Based on iRECIST | 0 percentage of participants |
| Dose Escalation Part: E7766 780 mcg | Dose Escalation Part: ORR Based on iRECIST | 0 percentage of participants |
| Dose Escalation Part: E7766 1000 mcg | Dose Escalation Part: ORR Based on iRECIST | 0 percentage of participants |
Secondary
Dose Escalation Part: ORR Based on mRECIST v1.1
ORR was defined as the percentage of participants with a BOR of CR or PR for target and non-target lesions. CR was defined as the disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in the short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. The tumor assessment was done using number of lesions based on modified RECIST 1.1 as per investigator assessment for assessing tumor burden up to 10 target lesions with up to 5 target lesions per organ.
Time frame: From date of first dose of study drug until confirmed CR or PR (up to 6 months and 18 days)
Population: The full analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Part: E7766 75 mcg | Dose Escalation Part: ORR Based on mRECIST v1.1 | 0 percentage of participants |
| Dose Escalation Part: E7766 150 mcg | Dose Escalation Part: ORR Based on mRECIST v1.1 | 0 percentage of participants |
| Dose Escalation Part: E7766 300 mcg | Dose Escalation Part: ORR Based on mRECIST v1.1 | 0 percentage of participants |
| Dose Escalation Part: E7766 600 mcg | Dose Escalation Part: ORR Based on mRECIST v1.1 | 0 percentage of participants |
| Dose Escalation Part: E7766 780 mcg | Dose Escalation Part: ORR Based on mRECIST v1.1 | 0 percentage of participants |
| Dose Escalation Part: E7766 1000 mcg | Dose Escalation Part: ORR Based on mRECIST v1.1 | 0 percentage of participants |
Secondary
Dose Escalation Part: Percentage (Fraction) Excreted (fe) in Feces for E7766
fe was defined as fraction of administered drug (E7766) excreted/recovered in feces. fe was quantified using validated liquid LC-MS/MS methods.
Time frame: Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length=21 days)
Population: The PK analysis set included the group of participants who have received at least 1 dose of study drug and have at least 1 evaluable plasma concentration. As planned, this outcome measure was assessed in dose escalation part only. Here overall number analyzed N were the participants who were evaluable for the outcome measure and number analyzed n are the participants who were evaluable for given timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Part: E7766 75 mcg | Dose Escalation Part: Percentage (Fraction) Excreted (fe) in Feces for E7766 | Cycle 1 Day 1 | 0.759 percentage of dose | Geometric Coefficient of Variation 390 |
| Dose Escalation Part: E7766 150 mcg | Dose Escalation Part: Percentage (Fraction) Excreted (fe) in Feces for E7766 | Cycle 1 Day 1 | 0.573 percentage of dose | — |
| Dose Escalation Part: E7766 600 mcg | Dose Escalation Part: Percentage (Fraction) Excreted (fe) in Feces for E7766 | Cycle 1 Day 1 | 0.0323 percentage of dose | — |
| Dose Escalation Part: E7766 780 mcg | Dose Escalation Part: Percentage (Fraction) Excreted (fe) in Feces for E7766 | Cycle 1 Day 1 | 0.0274 percentage of dose | Geometric Coefficient of Variation 85.5 |
| Dose Escalation Part: E7766 1000 mcg | Dose Escalation Part: Percentage (Fraction) Excreted (fe) in Feces for E7766 | Cycle 1 Day 1 | 0.0963 percentage of dose | — |
Secondary
Dose Escalation Part: Percentage (Fraction) Excreted (fe) in Urine for E7766
fe was defined as fraction of administered drug (E7766) excreted/recovered in urine. fe was quantified using validated liquid LC-MS/MS methods.
Time frame: Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length=21 days)
Population: The PK analysis set included the group of participants who have received at least 1 dose of study drug and have at least 1 evaluable plasma concentration. As planned, this outcome measure was assessed in dose escalation part only. Here overall number analyzed N were the participants who were evaluable for the outcome measure and number analyzed n are the participants who were evaluable for given timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Part: E7766 75 mcg | Dose Escalation Part: Percentage (Fraction) Excreted (fe) in Urine for E7766 | Cycle 1 Day 1 | 0.0786 percentage of dose | Geometric Coefficient of Variation 340 |
| Dose Escalation Part: E7766 75 mcg | Dose Escalation Part: Percentage (Fraction) Excreted (fe) in Urine for E7766 | Cycle 1 Day 15 | 0.0205 percentage of dose | Geometric Coefficient of Variation 874 |
| Dose Escalation Part: E7766 150 mcg | Dose Escalation Part: Percentage (Fraction) Excreted (fe) in Urine for E7766 | Cycle 1 Day 15 | 0.386 percentage of dose | — |
| Dose Escalation Part: E7766 150 mcg | Dose Escalation Part: Percentage (Fraction) Excreted (fe) in Urine for E7766 | Cycle 1 Day 1 | 0.0412 percentage of dose | — |
| Dose Escalation Part: E7766 300 mcg | Dose Escalation Part: Percentage (Fraction) Excreted (fe) in Urine for E7766 | Cycle 1 Day 15 | 0.302 percentage of dose | — |
| Dose Escalation Part: E7766 300 mcg | Dose Escalation Part: Percentage (Fraction) Excreted (fe) in Urine for E7766 | Cycle 1 Day 1 | 0.0429 percentage of dose | Geometric Coefficient of Variation 12.2 |
| Dose Escalation Part: E7766 600 mcg | Dose Escalation Part: Percentage (Fraction) Excreted (fe) in Urine for E7766 | Cycle 1 Day 15 | 0.279 percentage of dose | Geometric Coefficient of Variation 167 |
| Dose Escalation Part: E7766 600 mcg | Dose Escalation Part: Percentage (Fraction) Excreted (fe) in Urine for E7766 | Cycle 1 Day 1 | 0.0935 percentage of dose | Geometric Coefficient of Variation 799 |
| Dose Escalation Part: E7766 780 mcg | Dose Escalation Part: Percentage (Fraction) Excreted (fe) in Urine for E7766 | Cycle 1 Day 15 | 0.0655 percentage of dose | Geometric Coefficient of Variation 30.8 |
| Dose Escalation Part: E7766 780 mcg | Dose Escalation Part: Percentage (Fraction) Excreted (fe) in Urine for E7766 | Cycle 1 Day 1 | 0.0504 percentage of dose | Geometric Coefficient of Variation 41.8 |
| Dose Escalation Part: E7766 1000 mcg | Dose Escalation Part: Percentage (Fraction) Excreted (fe) in Urine for E7766 | Cycle 1 Day 1 | 0.0279 percentage of dose | — |
Secondary
Dose Escalation Part: Rac (AUC0-t): Accumulation Ratio Based on AUC for E7766
Rac (AUC0-t) was calculated as the ratio of AUC(0-t) on Cycle 1 Day 15 divided by AUC(0-t) on Cycle 1 Day 1. Accumulation ratio was quantified using validated liquid LC-MS/MS methods.
Time frame: Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length=21 days)
Population: The PK analysis set included the group of participants who have received at least 1 dose of study drug and have at least 1 evaluable plasma concentration. As planned, this outcome measure was assessed in dose escalation part only. Here overall number analyzed N were the participants who were evaluable for the outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation Part: E7766 75 mcg | Dose Escalation Part: Rac (AUC0-t): Accumulation Ratio Based on AUC for E7766 | 0.198 ratio | Geometric Coefficient of Variation 149 |
| Dose Escalation Part: E7766 150 mcg | Dose Escalation Part: Rac (AUC0-t): Accumulation Ratio Based on AUC for E7766 | 0.571 ratio | Geometric Coefficient of Variation 30.9 |
| Dose Escalation Part: E7766 300 mcg | Dose Escalation Part: Rac (AUC0-t): Accumulation Ratio Based on AUC for E7766 | 1.08 ratio | — |
| Dose Escalation Part: E7766 600 mcg | Dose Escalation Part: Rac (AUC0-t): Accumulation Ratio Based on AUC for E7766 | 0.527 ratio | Geometric Coefficient of Variation 127 |
| Dose Escalation Part: E7766 780 mcg | Dose Escalation Part: Rac (AUC0-t): Accumulation Ratio Based on AUC for E7766 | 0.907 ratio | Geometric Coefficient of Variation 17.2 |
Secondary
Dose Escalation Part: Rac (Cmax): Accumulation Ratio Based on Cmax for E7766
Rac (Cmax) was calculated as the ratio of Cmax on Cycle 1 Day 15 divided by Cmax on Cycle 1 Day 1. Accumulation ratio was quantified using validated liquid LC-MS/MS methods.
Time frame: Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length=21 days)
Population: The PK analysis set included the group of participants who have received at least 1 dose of study drug and have at least 1 evaluable plasma concentration. As planned, this outcome measure was assessed in dose escalation part only. Here overall number analyzed N were the participants who were evaluable for the outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation Part: E7766 75 mcg | Dose Escalation Part: Rac (Cmax): Accumulation Ratio Based on Cmax for E7766 | 0.305 ratio | Geometric Coefficient of Variation 126 |
| Dose Escalation Part: E7766 150 mcg | Dose Escalation Part: Rac (Cmax): Accumulation Ratio Based on Cmax for E7766 | 0.805 ratio | Geometric Coefficient of Variation 67.4 |
| Dose Escalation Part: E7766 300 mcg | Dose Escalation Part: Rac (Cmax): Accumulation Ratio Based on Cmax for E7766 | 1.43 ratio | — |
| Dose Escalation Part: E7766 600 mcg | Dose Escalation Part: Rac (Cmax): Accumulation Ratio Based on Cmax for E7766 | 0.339 ratio | Geometric Coefficient of Variation 117 |
| Dose Escalation Part: E7766 780 mcg | Dose Escalation Part: Rac (Cmax): Accumulation Ratio Based on Cmax for E7766 | 0.892 ratio | Geometric Coefficient of Variation 10.4 |
Secondary
Dose Escalation Part: Vd/F: Apparent Volume of Distribution for E7766
Vd/F was quantified using validated liquid LC-MS/MS methods.
Time frame: Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length=21 days)
Population: The PK analysis set included the group of participants who have received at least 1 dose of study drug and have at least 1 evaluable plasma concentration. As planned, this outcome measure was assessed in dose escalation part only. Here overall number analyzed N were the participants who were evaluable for the outcome measure and number analyzed n are the participants who were evaluable for given timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Part: E7766 150 mcg | Dose Escalation Part: Vd/F: Apparent Volume of Distribution for E7766 | Cycle 1 Day 1 | 60.4 liter | — |
| Dose Escalation Part: E7766 150 mcg | Dose Escalation Part: Vd/F: Apparent Volume of Distribution for E7766 | Cycle 1 Day 15 | 94.8 liter | Geometric Coefficient of Variation 20 |
| Dose Escalation Part: E7766 300 mcg | Dose Escalation Part: Vd/F: Apparent Volume of Distribution for E7766 | Cycle 1 Day 15 | 68.6 liter | — |
| Dose Escalation Part: E7766 300 mcg | Dose Escalation Part: Vd/F: Apparent Volume of Distribution for E7766 | Cycle 1 Day 1 | 100.0 liter | Geometric Coefficient of Variation 29.5 |
| Dose Escalation Part: E7766 600 mcg | Dose Escalation Part: Vd/F: Apparent Volume of Distribution for E7766 | Cycle 1 Day 15 | 225.0 liter | Geometric Coefficient of Variation 80 |
| Dose Escalation Part: E7766 600 mcg | Dose Escalation Part: Vd/F: Apparent Volume of Distribution for E7766 | Cycle 1 Day 1 | 127.0 liter | Geometric Coefficient of Variation 65.9 |
| Dose Escalation Part: E7766 780 mcg | Dose Escalation Part: Vd/F: Apparent Volume of Distribution for E7766 | Cycle 1 Day 15 | 115.0 liter | Geometric Coefficient of Variation 40.8 |
| Dose Escalation Part: E7766 780 mcg | Dose Escalation Part: Vd/F: Apparent Volume of Distribution for E7766 | Cycle 1 Day 1 | 145.0 liter | Geometric Coefficient of Variation 50.5 |
| Dose Escalation Part: E7766 1000 mcg | Dose Escalation Part: Vd/F: Apparent Volume of Distribution for E7766 | Cycle 1 Day 1 | 131.0 liter | — |
Secondary
Overall Survival (OS)
OS was measured from the date of first dose of study drug until date of death from any cause. OS event was defined as deaths no later than data cut off date or date of death of a participant.
Time frame: From first dose of study drug until confirmed PD or death up to 6 months 18 days (Dose Escalation Part) and up to 29 months (Dose Expansion Part)
Population: The full analysis set included all participants who received at least 1 dose of study drug. No participants were enrolled in the Dose Expansion part. Hence, no data collection and analysis were done during Dose Expansion part.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation Part: E7766 75 mcg | Overall Survival (OS) | NA months |
| Dose Escalation Part: E7766 150 mcg | Overall Survival (OS) | NA months |
| Dose Escalation Part: E7766 300 mcg | Overall Survival (OS) | NA months |
| Dose Escalation Part: E7766 600 mcg | Overall Survival (OS) | NA months |
| Dose Escalation Part: E7766 780 mcg | Overall Survival (OS) | NA months |
| Dose Escalation Part: E7766 1000 mcg | Overall Survival (OS) | NA months |
Secondary
Part: AUC(0-t): Area Under the Plasma Concentration From Time Zero to Last Curve for E7766
AUC was quantified using validated liquid LC-MS/MS methods.
Time frame: Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose; Dose Expansion: Cycle 1 Days 1 and 15: predose up to 2 hours postdose (Cycle length=21 days)
Population: The PK analysis set included the group of participants who have received at least 1 dose of study drug and have at least 1 evaluable plasma concentration. No participants were enrolled in the Dose Expansion part. Hence, no data collection and analysis were done during Dose Expansion part. Here number analyzed n are the participants who were evaluable for this outcome measure for given timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Part: E7766 75 mcg | Part: AUC(0-t): Area Under the Plasma Concentration From Time Zero to Last Curve for E7766 | Cycle 1 Day 15 | 0.536 hour*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 17 |
| Dose Escalation Part: E7766 75 mcg | Part: AUC(0-t): Area Under the Plasma Concentration From Time Zero to Last Curve for E7766 | Cycle 1 Day 1 | 2.71 hour*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 114 |
| Dose Escalation Part: E7766 150 mcg | Part: AUC(0-t): Area Under the Plasma Concentration From Time Zero to Last Curve for E7766 | Cycle 1 Day 15 | 1.95 hour*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 29.4 |
| Dose Escalation Part: E7766 150 mcg | Part: AUC(0-t): Area Under the Plasma Concentration From Time Zero to Last Curve for E7766 | Cycle 1 Day 1 | 3.42 hour*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 64.7 |
| Dose Escalation Part: E7766 300 mcg | Part: AUC(0-t): Area Under the Plasma Concentration From Time Zero to Last Curve for E7766 | Cycle 1 Day 1 | 4.25 hour*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 26.6 |
| Dose Escalation Part: E7766 300 mcg | Part: AUC(0-t): Area Under the Plasma Concentration From Time Zero to Last Curve for E7766 | Cycle 1 Day 15 | 5.51 hour*nanograms per milliliter (h*ng/mL) | — |
| Dose Escalation Part: E7766 600 mcg | Part: AUC(0-t): Area Under the Plasma Concentration From Time Zero to Last Curve for E7766 | Cycle 1 Day 1 | 7.7 hour*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 35.9 |
| Dose Escalation Part: E7766 600 mcg | Part: AUC(0-t): Area Under the Plasma Concentration From Time Zero to Last Curve for E7766 | Cycle 1 Day 15 | 4.06 hour*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 101 |
| Dose Escalation Part: E7766 780 mcg | Part: AUC(0-t): Area Under the Plasma Concentration From Time Zero to Last Curve for E7766 | Cycle 1 Day 15 | 6.89 hour*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 76.9 |
| Dose Escalation Part: E7766 780 mcg | Part: AUC(0-t): Area Under the Plasma Concentration From Time Zero to Last Curve for E7766 | Cycle 1 Day 1 | 8.29 hour*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 44.2 |
| Dose Escalation Part: E7766 1000 mcg | Part: AUC(0-t): Area Under the Plasma Concentration From Time Zero to Last Curve for E7766 | Cycle 1 Day 1 | 10.3 hour*nanograms per milliliter (h*ng/mL) | — |
Secondary
Percent Change From Baseline in Tumor Size
Percent change from baseline in tumor size was calculated for the first injected lesion based on Investigator Assessment.
Time frame: Baseline to up to 6 months and 18 days (Dose Escalation Part) and up to 29 months (Dose Expansion Part)
Population: The full analysis set included all participants who received at least 1 dose of study drug. No participants were enrolled in the Dose Expansion part. Hence, no data collection and analysis were done during Dose Expansion part.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dose Escalation Part: E7766 75 mcg | Percent Change From Baseline in Tumor Size | NA percent change |
| Dose Escalation Part: E7766 150 mcg | Percent Change From Baseline in Tumor Size | NA percent change |
| Dose Escalation Part: E7766 300 mcg | Percent Change From Baseline in Tumor Size | NA percent change |
| Dose Escalation Part: E7766 600 mcg | Percent Change From Baseline in Tumor Size | NA percent change |
| Dose Escalation Part: E7766 780 mcg | Percent Change From Baseline in Tumor Size | NA percent change |
| Dose Escalation Part: E7766 1000 mcg | Percent Change From Baseline in Tumor Size | NA percent change |
Secondary
PFS Based on iRECIST
PFS was defined as the time from the first dose date to the date of iPD or date of death (whichever occurred first) according to iRECIST version 1.1 as per investigator assessment. iCPD: immune confirmed progressive disease when there is either 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: From first dose of study drug until confirmed PD or death up to 6 months 18 days (Dose Escalation Part) and up to 29 months (Dose Expansion Part)
Population: The full analysis set included all participants who received at least 1 dose of study drug. No participants were enrolled in the Dose Expansion part. Hence, no data collection and analysis were done during Dose Expansion part.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation Part: E7766 75 mcg | PFS Based on iRECIST | NA months |
| Dose Escalation Part: E7766 150 mcg | PFS Based on iRECIST | NA months |
| Dose Escalation Part: E7766 300 mcg | PFS Based on iRECIST | NA months |
| Dose Escalation Part: E7766 600 mcg | PFS Based on iRECIST | NA months |
| Dose Escalation Part: E7766 780 mcg | PFS Based on iRECIST | NA months |
| Dose Escalation Part: E7766 1000 mcg | PFS Based on iRECIST | NA months |
Secondary
Progression Free Survival (PFS) Based on mRECIST v1.1
PFS was defined as the time from the first study dose date to the date of first documentation of disease progression or death (whichever occurred first) based on mRECIST v1.1 as per investigator assessment. PD was defined as at least a 20% increase in the sum of LD of target and non-target lesions as compared with the smallest sum of LD and the increase of LD was at least 5 mm (including new lesions).
Time frame: From first dose of study drug until confirmed PD or death up to 6 months 18 days (Dose Escalation Part) and up to 29 months (Dose Expansion Part)
Population: The full analysis set included all participants who received at least 1 dose of study drug. No participants were enrolled in the Dose Expansion part. Hence, no data collection and analysis were done during Dose Expansion part.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation Part: E7766 75 mcg | Progression Free Survival (PFS) Based on mRECIST v1.1 | NA months |
| Dose Escalation Part: E7766 150 mcg | Progression Free Survival (PFS) Based on mRECIST v1.1 | NA months |
| Dose Escalation Part: E7766 300 mcg | Progression Free Survival (PFS) Based on mRECIST v1.1 | NA months |
| Dose Escalation Part: E7766 600 mcg | Progression Free Survival (PFS) Based on mRECIST v1.1 | NA months |
| Dose Escalation Part: E7766 780 mcg | Progression Free Survival (PFS) Based on mRECIST v1.1 | NA months |
| Dose Escalation Part: E7766 1000 mcg | Progression Free Survival (PFS) Based on mRECIST v1.1 | NA months |
Secondary
t1/2: Terminal Elimination Half-life for E7766
t1/2 was quantified using validated liquid LC-MS/MS methods.
Time frame: Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose; Dose Expansion: Cycle 1 Days 1 and 15: predose up to 2 hours postdose (Cycle length=21 days)
Population: The PK analysis set included the group of participants who have received at least 1 dose of study drug and have at least 1 evaluable plasma concentration. No participants were enrolled in the Dose Expansion part. Hence, no data collection and analysis were done during Dose Expansion part. Here overall number analyzed N were the participants who were evaluable for the outcome measure and number analyzed n are the participants who were evaluable for given timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Part: E7766 150 mcg | t1/2: Terminal Elimination Half-life for E7766 | Cycle 1 Day 1 | 1.56 hour | — |
| Dose Escalation Part: E7766 150 mcg | t1/2: Terminal Elimination Half-life for E7766 | Cycle 1 Day 15 | 0.956 hour | Geometric Coefficient of Variation 58.1 |
| Dose Escalation Part: E7766 300 mcg | t1/2: Terminal Elimination Half-life for E7766 | Cycle 1 Day 15 | 0.917 hour | — |
| Dose Escalation Part: E7766 300 mcg | t1/2: Terminal Elimination Half-life for E7766 | Cycle 1 Day 1 | 1.07 hour | Geometric Coefficient of Variation 4.61 |
| Dose Escalation Part: E7766 600 mcg | t1/2: Terminal Elimination Half-life for E7766 | Cycle 1 Day 15 | 1.34 hour | Geometric Coefficient of Variation 66.7 |
| Dose Escalation Part: E7766 600 mcg | t1/2: Terminal Elimination Half-life for E7766 | Cycle 1 Day 1 | 1.18 hour | Geometric Coefficient of Variation 36.9 |
| Dose Escalation Part: E7766 780 mcg | t1/2: Terminal Elimination Half-life for E7766 | Cycle 1 Day 15 | 0.723 hour | Geometric Coefficient of Variation 59.5 |
| Dose Escalation Part: E7766 780 mcg | t1/2: Terminal Elimination Half-life for E7766 | Cycle 1 Day 1 | 1.15 hour | Geometric Coefficient of Variation 17.5 |
| Dose Escalation Part: E7766 1000 mcg | t1/2: Terminal Elimination Half-life for E7766 | Cycle 1 Day 1 | 1 hour | — |
Secondary
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for E7766
Tmax was quantified using validated liquid LC-MS/MS methods.
Time frame: Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose; Dose Expansion: Cycle 1 Days 1 and 15: predose up to 2 hours postdose (Cycle length=21 days)
Population: The PK analysis set included the group of participants who have received at least 1 dose of study drug and have at least 1 evaluable plasma concentration. No participants were enrolled in the Dose Expansion part. Hence, no data collection and analysis were done during Dose Expansion part.Here number analyzed n are the participants who were evaluable for this outcome measure for given timepoints.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dose Escalation Part: E7766 75 mcg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for E7766 | Cycle 1 Day 1 | 0.275 hours |
| Dose Escalation Part: E7766 75 mcg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for E7766 | Cycle 1 Day 15 | 0.215 hours |
| Dose Escalation Part: E7766 150 mcg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for E7766 | Cycle 1 Day 15 | 0.385 hours |
| Dose Escalation Part: E7766 150 mcg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for E7766 | Cycle 1 Day 1 | 0.31 hours |
| Dose Escalation Part: E7766 300 mcg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for E7766 | Cycle 1 Day 15 | 0.25 hours |
| Dose Escalation Part: E7766 300 mcg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for E7766 | Cycle 1 Day 1 | 0.275 hours |
| Dose Escalation Part: E7766 600 mcg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for E7766 | Cycle 1 Day 15 | 0.25 hours |
| Dose Escalation Part: E7766 600 mcg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for E7766 | Cycle 1 Day 1 | 0.25 hours |
| Dose Escalation Part: E7766 780 mcg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for E7766 | Cycle 1 Day 15 | 0.21 hours |
| Dose Escalation Part: E7766 780 mcg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for E7766 | Cycle 1 Day 1 | 0.25 hours |
| Dose Escalation Part: E7766 1000 mcg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for E7766 | Cycle 1 Day 1 | 0.28 hours |