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

Phase 1TerminatedNCT04144140

Eisai Inc.24 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Lymphoma Advanced Solid Tumors

Interventions

E7766DRUG

E7766, solution, intratumorally

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (13)

Yale New Haven Hospital

New Haven, Connecticut, United States

University of Miami Hospital Sylvester Comprehensive Cancer Center

Miami, Florida, United States

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, United States

Outcomes

Primary Outcomes

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)

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)

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.

Data from ClinicalTrials.gov

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Secondary Outcomes

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

Dose Escalation Part: CL/F: Apparent Total Body Clearance for E7766

CL/F was quantified using validated liquid LC-MS/MS methods.