Clinical trial NCT04144140: Study of Intratumorally Administered Stimulator of Interferon Genes (STING) Agonist E7766 in Participants With Advanced Solid Tumors or Lymphomas - INSTAL-101
Official title: An Open-Label, Multicenter Phase 1/1b Study of Intratumorally Administered STING Agonist E7766 in Subjects With Advanced Solid Tumors or Lymphomas - INSTAL-101
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Lymphoma
Advanced Solid Tumors
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
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
Collaborators: name: H3 Biomedicine Inc.
First posted: 2019-10-30
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: Dose Escalation Part: Number of Participants With Dose-limiting Toxicities (DLTs)
timeFrame: Cycle 1 (Cycle length= 21 days)
measure: Number of Participants With Any Treatment-emergent Adverse Events (TEAEs)
timeFrame: From the first dose of the study drug up to 90 days after the last dose (up to 9 months and 14 days)
measure: Dose Expansion Part: Objective Response Rate Based on Modified Response Evaluation Criteria In Solid Tumors (mRECIST) v1.1
timeFrame: From date of first dose of study drug until confirmed CR or PR (up to 29 months)
measure: Dose Expansion Part: ORR Based on Immune Response Evaluation Criteria in Solid Tumors (iRECIST)
timeFrame: From date of first dose of study drug until confirmed iCR or iPR (up to 29 months)
measure: Dose Expansion Part: Duration of Response (DOR) Based on mRECIST v1.1
timeFrame: From first documented confirmed CR or PR until first documentation of PD or death (up to 29 months)
measure: Dose Expansion Part: DOR Based on iRECIST
timeFrame: From first documented confirmed iCR or iPR until first documentation of iPD or death (up to 29 months)
measure: Dose Expansion Part: Disease Control Rate (DCR) Based on mRECIST v1.1
timeFrame: From first dose of study drug until confirmed CR or PR or >=5 weeks after first dose for SD (up to 29 months)
measure: Dose Expansion Part: DCR Based on iRECIST
timeFrame: From first dose of study drug until confirmed iCR or iPR or >=5 weeks after first dose for iSD (up to 29 months)
Secondary outcomes:
measure: Dose Escalation Part: ORR Based on iRECIST
timeFrame: From date of first dose of study drug until confirmed iCR or iPR (up to 6 months and 18 days)
measure: Dose Escalation Part: ORR Based on mRECIST v1.1
timeFrame: From date of first dose of study drug until confirmed CR or PR (up to 6 months and 18 days)
measure: Dose Escalation Part: DOR Based on iRECIST
timeFrame: From first documented confirmed iCR or iPR until first documentation of iPD or death (up to 6 months and 18 days)
measure: Dose Escalation Part: DOR Based on mRECIST v1.1
timeFrame: From first documented confirmed CR or PR until first documentation of PD or death (up to 6 months and 18 days)
measure: Dose Escalation Part: DCR Based on iRECIST
timeFrame: 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)
measure: Dose Escalation Part: DCR Based on mRECIST v1.1
timeFrame: 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)
measure: Cmax: Maximum Observed Plasma Concentration for E7766
timeFrame: 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)
measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for E7766
timeFrame: 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)
measure: Part: AUC(0-t): Area Under the Plasma Concentration From Time Zero to Last Curve for E7766
timeFrame: 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)
measure: AUC(0-inf): Area Under the Plasma Concentration From Time Zero to Infinity Curve for E7766
timeFrame: 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)
measure: t1/2: Terminal Elimination Half-life for E7766
timeFrame: 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)
measure: Dose Escalation Part: CL/F: Apparent Total Body Clearance for E7766
timeFrame: Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length=21 days)
measure: Dose Escalation Part: Vd/F: Apparent Volume of Distribution for E7766
timeFrame: Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length=21 days)
measure: Dose Escalation Part: CLr: Renal Clearance for E7766
timeFrame: Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length=21 days)
measure: Dose Escalation Part: Rac (Cmax): Accumulation Ratio Based on Cmax for E7766
timeFrame: Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length=21 days)
measure: Dose Escalation Part: Rac (AUC0-t): Accumulation Ratio Based on AUC for E7766
timeFrame: Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length=21 days)
measure: Dose Escalation Part: Percentage (Fraction) Excreted (fe) in Urine for E7766
timeFrame: Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length=21 days)
measure: Dose Escalation Part: Percentage (Fraction) Excreted (fe) in Feces for E7766
timeFrame: Dose Escalation: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length=21 days)
measure: Progression Free Survival (PFS) Based on mRECIST v1.1
timeFrame: 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)
measure: PFS Based on iRECIST
timeFrame: 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)
measure: Overall Survival (OS)
timeFrame: 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)
measure: Percent Change From Baseline in Tumor Size
timeFrame: Baseline to up to 6 months and 18 days (Dose Escalation Part) and up to 29 months (Dose Expansion Part)
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale New Haven Hospital
state: Connecticut
city: Miami
country: United States
facility: University of Miami Hospital Sylvester Comprehensive Cancer Center
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center and Hillman Cancer Center
state: Pennsylvania
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebrón
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: START Madrid
city: Valencia
country: Spain
facility: INCLIVA Hospital Clínico Universitario de Valencia
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust
Study officials:
References: