Study of Intratumorally Administered Stimulator of Interferon Genes (STING) Agonist E7766 in Participants With Advanced Solid Tumors or Lymphomas - INSTAL-101

Phase 1

Terminated

Conditions: Lymphoma
Advanced Solid Tumors

Interventions: Drug: E7766

Registration Number: NCT04144140

Lead Sponsor: Eisai Inc.

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 24

Inclusion Criteria

Not provided

Exclusion Criteria

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.
Known human immunodeficiency virus (HIV) infection.
Major surgery within 4 weeks before the first dose of study drug.
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.
Prolongation of corrected QT (QTc) interval to >450 millisecond (msec) for males and females when electrolytes balance is normal.
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.
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.
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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Dose Escalation: Advanced Solid Tumors or Lymphomas	E7766	-
Dose Expansion: Advanced Solid Tumors or Lymphomas	E7766	Dose identified from dose escalation part for E7766 will be used in dose expansion part.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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.
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.
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.
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.
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: 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: 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.

Trial Locations

Locations (13): University of Pittsburgh Medical Center and Hillman Cancer Center
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Pittsburgh, Pennsylvania, United States
Massachusetts General Hospital Cancer Center
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Boston, Massachusetts, United States
Samsung Medical Center
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Seoul, Korea, Republic of
Yale New Haven Hospital
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New Haven, Connecticut, United States
Beth Israel Deaconess Medical Center
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Boston, Massachusetts, United States
Dana-Farber Cancer Institute
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Boston, Massachusetts, United States
INCLIVA Hospital Clínico Universitario de Valencia
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Valencia, Spain
University of Miami Hospital Sylvester Comprehensive Cancer Center
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Miami, Florida, United States
Hospital Universitario Vall d'Hebrón
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Barcelona, Spain
Institut Gustave Roussy
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Villejuif, France
Hospital Universitario 12 de Octubre
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Madrid, Spain
Imperial College Healthcare NHS Trust
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London, United Kingdom
START Madrid
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Madrid, Spain