Solid Tumor
Conditions
Keywords
TIM-3, PD-L1
Brief summary
The goal of this study is to evaluate the safety of LY3415244, a PD-L1/TIM-3 bispecific antibody, administered as monotherapy to participants with advanced solid tumors.
Interventions
DRUGLY3415244
Administered IV
Sponsors
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* For Phase 1a/b, histologic or cytologic confirmation of advanced solid tumor. * For Phase 1a/b, biopsy of tumor samples are required. Newly obtained core or excisional biopsy of a tumor lesion prior to study enrollment and undergo a biopsy procedure during the study. * Phase 1a, prior anti-PD-1 or anti-PD-L1 therapy or other immunotherapy is allowed. * Phase 1b, prior anti-PD-1 or anti-PD-L1 therapy is required where anti-PD-1 or anti-PD-L1 is standard of care in respective tumor types if the following criteria are met: * Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy * Must have completely recovered to baseline level prior to screening from any adverse events (AEs) that occurred from receiving prior immunotherapy * Must not have experienced a Grade ≥3 immune-related AE or immune related neurologic or ocular AE, pneumonitis or cardiomyopathy of any grade while receiving prior immunotherapy * Must not have required immunosuppressive agent, other than corticosteroids for the management of an adverse event and not currently require maintenance doses of \>10 milligrams (mg) prednisone (or equivalent) per day * Must have at least 1 measurable lesion as defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). * Have adequate organ function. * Have an estimated life expectancy ≥12 weeks, in the judgement of the investigator.
Exclusion criteria
* Have symptomatic central nervous system (CNS) malignancy or metastasis not requiring concurrent treatment, including but not limited to surgery, radiation, corticosteroids and/or anticonvulsants to treat CNS metastases, and their disease is asymptomatic and radiographically stable for at least 30 days. * Have received a live vaccine within 30 days before the first dose of study treatment. * If female, is pregnant, breastfeeding, or planning to become pregnant. * Have a history or current evidence of any condition, therapy, or laboratory abnormality that might interfere with the participant's participation. * Have moderate or severe cardiovascular disease. * Have a serious concomitant systemic disorder that would compromise the participant's ability to adhere to the protocol, including known infection with human immunodeficiency virus (HIV), active hepatitis B virus (HBV), active hepatitis C virus (HCV), active autoimmune disorders, or prior documented severe autoimmune or inflammatory disorders requiring immunosuppressive treatment. * Use of escalating or chronic supraphysiologic doses of corticosteroids or immunosuppressive agents (such as, cyclosporine). \[Use of topical, ophthalmic, inhaled, and intranasal corticosteroids permitted\]. * Bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection. * Evidence of interstitial lung disease or noninfectious pneumonitis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase1a: Number of Participants With LY3415244 Dose-Limiting Toxicities (DLTs) | Baseline through Cycle 1 (28 Day Cycle) | A DLT was defined as an adverse event (AE) occurring during Cycle 1(28 days) that was considered at least possibly related to study drug, was considered dose-dependent, and fulfilled a criteria selected (using the National Cancer Institute Common Terminology Criteria for Adverse Events,version 4.0 \[NCI-CTCAE v 4.0\] \[NCI 2009\]):Grade 3 thrombocytopenia requiring platelet transfusion or grade 4 thrombocytopenia. Grade greater than or equal to (≥) 3 febrile neutropenia, anemia requiring a blood transfusion and any other Grade 4 hematologic toxicity that last \>7 days. Grade ≥ 3 colitis or noninfectious pneumonitis, Grade ≥ 3 fatigue lasting \>7 days, Grade ≥ 3 hypertension despite of maximal medical therapy. Grade 4 immune-related adverse event (irAE), liver transaminase elevation \>8x upper limit of normal (ULN) or total bilirubin \>3x ULN. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase1b: Objective Response Rate (ORR): Percentage of Participants Who Achieve Complete Response (CR) or Partial Response (PR) | Baseline through Measured Progressive Disease (Up To 24 Months) | ORR was the percentage of participants achieving a best overall response (BOR) of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. PD was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. |
| Phase1b: Duration of Response (DoR) | Date of CR or PR to Date of Objective Disease Progression or Death Due to Any Cause (Up To 24 Months) | Duration of response was defined using RECIST v. 1.1 criteria as the time from the date criteria were met for the first objectively recorded CR or PR until the first date criteria for PD were met or death from any cause. CR was the disappearance of all lesions and pathological lymph node reduction in the short axis to \<10 mm. PR was a ≥30% decrease in the sum of the diameters of target lesions. PD was a ≥20% increase in the sum of the diameters of target lesions with the sum demonstrating an absolute increase of ≥5 mm; the appearance of ≥1 new lesions or unequivocal progression of non-target lesions. Participants who were not known to have died and who did not have PD were censored at the date of the last tumor assessment prior to the date of any subsequent systemic anticancer therapy. |
| Phase1a: Pharmacokinetics (PK): Minimum Concentration (Cmin) of LY3415244 | Cycle 1 Day 1 (C1D1) and C1D15: pre-dose, 2 hours(h), 4h, 24h, 72h, 120h and 168h post-dose; C2D1, C2D15, C3D1, C3D15, C4D1, C4D15, C5D1, C5D15, C6D1 and C6D15: pre-dose | Cmin of LY3415244 was evaluated. |
| Phase1b: Disease Control Rate (DCR): Percentage of Participants With a Best Overall Response of CR, PR, and Stable Disease | Baseline through Measured Progressive Disease (Up To 24 Months) | DCR is the percentage of participants with a best overall response of CR, PR or stable disease (SD) as defined by RECIST v1.1. CR is defined as disappearance of all target and non-target lesions and no appearance of new lesions.PR is defined as at least a 30% decrease in sum of longest diameter (LD) of target lesions (taking as reference the baseline sum LD),no progression of non-target lesions, and no appearance of new lesions.SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD) for target lesions, no progression of non-target lesions, and no appearance of new lesions. PD is defined as at least a 20% increase in the sum of diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm,or unequivocal progression of non-target lesions,or 1 or more new lesions. |
| Phase1b: Progression Free Survival (PFS) | Baseline to Objective Progression or Death Due to Any Cause (Up To 24 Months) | Progression-free survival time was measured from treatment start until the date of objective progression as defined by Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1), or death from any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. Patients who have neither progressed nor died were censored at the day of their last radiographic tumor assessment, if available, or date of treatment start if no post-baseline radiographic assessment is available. |
| Phase1b: Time to Response (TTR) | Baseline to Date of CR or PR (Up To 24 Months) | Data were not captured as study was terminated early and no participant were enrolled into Phase 1b expansion. Time to treatment response was defined as date of first dose of study drug to the date of confirmed complete response (CR) or partial response (PR) using Response evaluation Criteria in Solid Tumors (RECIST v1.0) criteria. CR was defined as the disappearance of all target and non-target lesions and normalization of tumor marker levels in non-target lesions. PR was defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. |
Countries
Belgium, Japan, United States
Participant flow
Pre-assignment details
Phase 1a of study consisted of dose-escalation assessment and Phase 1b of study included dose expansion. Four out of planned eight cohorts (one optional) in Phase 1a were completed. Phase 1b dose expansion was planned but not initiated as dose escalation ended at cohort A4.A participant completed study if they completed at least 1 cycle (28 days).
Participants by arm
| Arm | Count |
|---|---|
| Cohort A1 Participants received 3 milligrams (mg) LY3415244 as an intravenous (IV) infusion on day (D)1 and D15 of each 28-day cycle every 2 weeks (Q2W). | 3 |
| Cohort A2 Participants received 10 mg LY3415244 as an IV infusion on D1 and D15 of each 28-day cycle Q2W. | 3 |
| Cohort A3 Participants received 30 mg LY3415244 as an IV infusion on D1 and D15 of each 28-day cycle Q2W. | 3 |
| Cohort A4 Participants received 70 mg LY3415244 as an IV infusion on D1 and D15 of each 28-day cycle Q2W. | 3 |
| Total | 12 |
Baseline characteristics
| Characteristic | Cohort A1 | Cohort A2 | Cohort A3 | Cohort A4 | Total |
|---|---|---|---|---|---|
| Age, Continuous | 53.33 years STANDARD_DEVIATION 2.31 | 57.00 years STANDARD_DEVIATION 11.36 | 48.33 years STANDARD_DEVIATION 20.6 | 55.67 years STANDARD_DEVIATION 3.79 | 53.58 years STANDARD_DEVIATION 10.77 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 2 Participants | 3 Participants | 1 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 2 Participants | 3 Participants | 2 Participants | 8 Participants |
| Region of Enrollment Belgium | 0 Participants | 1 Participants | 2 Participants | 2 Participants | 5 Participants |
| Region of Enrollment Japan | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 4 Participants |
| Region of Enrollment United States | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 6 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 2 Participants | 2 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 0 / 3 | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 0 / 3 | 2 / 3 |
Outcome results
Primary
Phase1a: Number of Participants With LY3415244 Dose-Limiting Toxicities (DLTs)
A DLT was defined as an adverse event (AE) occurring during Cycle 1(28 days) that was considered at least possibly related to study drug, was considered dose-dependent, and fulfilled a criteria selected (using the National Cancer Institute Common Terminology Criteria for Adverse Events,version 4.0 \[NCI-CTCAE v 4.0\] \[NCI 2009\]):Grade 3 thrombocytopenia requiring platelet transfusion or grade 4 thrombocytopenia. Grade greater than or equal to (≥) 3 febrile neutropenia, anemia requiring a blood transfusion and any other Grade 4 hematologic toxicity that last \>7 days. Grade ≥ 3 colitis or noninfectious pneumonitis, Grade ≥ 3 fatigue lasting \>7 days, Grade ≥ 3 hypertension despite of maximal medical therapy. Grade 4 immune-related adverse event (irAE), liver transaminase elevation \>8x upper limit of normal (ULN) or total bilirubin \>3x ULN.
Time frame: Baseline through Cycle 1 (28 Day Cycle)
Population: All participants who received at least 1 dose of study drug and had evaluable DLT data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A1 | Phase1a: Number of Participants With LY3415244 Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Cohort A2 | Phase1a: Number of Participants With LY3415244 Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Cohort A3 | Phase1a: Number of Participants With LY3415244 Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Cohort A4 | Phase1a: Number of Participants With LY3415244 Dose-Limiting Toxicities (DLTs) | 0 Participants |
Secondary
Phase1a: Pharmacokinetics (PK): Minimum Concentration (Cmin) of LY3415244
Cmin of LY3415244 was evaluated.
Time frame: Cycle 1 Day 1 (C1D1) and C1D15: pre-dose, 2 hours(h), 4h, 24h, 72h, 120h and 168h post-dose; C2D1, C2D15, C3D1, C3D15, C4D1, C4D15, C5D1, C5D15, C6D1 and C6D15: pre-dose
Population: All participants who received at least 1 dose of study drug with evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A2 | Phase1a: Pharmacokinetics (PK): Minimum Concentration (Cmin) of LY3415244 | Cycle 1 Day 15 | NA nanograms per milliliter (ng/mL) | — |
| Cohort A3 | Phase1a: Pharmacokinetics (PK): Minimum Concentration (Cmin) of LY3415244 | Cycle 1 Day 1 | NA nanograms per milliliter (ng/mL) | — |
| Cohort A3 | Phase1a: Pharmacokinetics (PK): Minimum Concentration (Cmin) of LY3415244 | Cycle 1 Day 15 | NA nanograms per milliliter (ng/mL) | — |
| Cohort A4 | Phase1a: Pharmacokinetics (PK): Minimum Concentration (Cmin) of LY3415244 | Cycle 1 Day 1 | 4270 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 26 |
Secondary
Phase1b: Disease Control Rate (DCR): Percentage of Participants With a Best Overall Response of CR, PR, and Stable Disease
DCR is the percentage of participants with a best overall response of CR, PR or stable disease (SD) as defined by RECIST v1.1. CR is defined as disappearance of all target and non-target lesions and no appearance of new lesions.PR is defined as at least a 30% decrease in sum of longest diameter (LD) of target lesions (taking as reference the baseline sum LD),no progression of non-target lesions, and no appearance of new lesions.SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD) for target lesions, no progression of non-target lesions, and no appearance of new lesions. PD is defined as at least a 20% increase in the sum of diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm,or unequivocal progression of non-target lesions,or 1 or more new lesions.
Time frame: Baseline through Measured Progressive Disease (Up To 24 Months)
Population: Zero participants were analyzed for this outcome. Data were not captured as study was terminated early and no participant were enrolled into Phase 1b expansion.
Secondary
Phase1b: Duration of Response (DoR)
Duration of response was defined using RECIST v. 1.1 criteria as the time from the date criteria were met for the first objectively recorded CR or PR until the first date criteria for PD were met or death from any cause. CR was the disappearance of all lesions and pathological lymph node reduction in the short axis to \<10 mm. PR was a ≥30% decrease in the sum of the diameters of target lesions. PD was a ≥20% increase in the sum of the diameters of target lesions with the sum demonstrating an absolute increase of ≥5 mm; the appearance of ≥1 new lesions or unequivocal progression of non-target lesions. Participants who were not known to have died and who did not have PD were censored at the date of the last tumor assessment prior to the date of any subsequent systemic anticancer therapy.
Time frame: Date of CR or PR to Date of Objective Disease Progression or Death Due to Any Cause (Up To 24 Months)
Population: Zero participants were analyzed for this outcome. Data were not captured as study was terminated early and no participant were enrolled into Phase 1b expansion.
Secondary
Phase1b: Objective Response Rate (ORR): Percentage of Participants Who Achieve Complete Response (CR) or Partial Response (PR)
ORR was the percentage of participants achieving a best overall response (BOR) of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. PD was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.
Time frame: Baseline through Measured Progressive Disease (Up To 24 Months)
Population: Zero participants were analyzed for this outcome. Data were not captured as study was terminated early and no participant were enrolled into Phase 1b expansion.
Secondary
Phase1b: Progression Free Survival (PFS)
Progression-free survival time was measured from treatment start until the date of objective progression as defined by Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1), or death from any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. Patients who have neither progressed nor died were censored at the day of their last radiographic tumor assessment, if available, or date of treatment start if no post-baseline radiographic assessment is available.
Time frame: Baseline to Objective Progression or Death Due to Any Cause (Up To 24 Months)
Population: Zero participants were analyzed for this outcome. Data were not captured as study was terminated early and no participant were enrolled into Phase 1b expansion.
Secondary
Phase1b: Time to Response (TTR)
Data were not captured as study was terminated early and no participant were enrolled into Phase 1b expansion. Time to treatment response was defined as date of first dose of study drug to the date of confirmed complete response (CR) or partial response (PR) using Response evaluation Criteria in Solid Tumors (RECIST v1.0) criteria. CR was defined as the disappearance of all target and non-target lesions and normalization of tumor marker levels in non-target lesions. PR was defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.
Time frame: Baseline to Date of CR or PR (Up To 24 Months)
Population: Zero participants were analyzed for this outcome. Data were not captured as study was terminated early and no participant were enrolled into Phase 1b expansion.