Advanced Solid Cancers, Advanced Solid Cancers Refractory to PD-1 and PD-L1 Therapies
Conditions
Brief summary
This is an open-label, Phase 1/2, multicenter study to evaluate the safety, pharmacokinetics, and pharmacodynamics of an anti-cytotoxic T lymphocyte-associated protein-4 (CTLA-4) human monoclonal antibody (zalifrelimab) in participants with advanced or refractory cancer and in participants who have progressed during treatment with a programmed cell death protein-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitor as their most recent therapy. The phase 1 portion of the study has been completed; it enrolled adult participants with refractory, advanced cancer in a 3+3 dose escalation cohort. The phase 2 portion consisted of 51 participants who progressed during treatment with an approved or investigational PD-1/PD-L1 inhibitor as their most recent therapy (2-6 weeks prior to first dose of study drug).
Interventions
DRUGZalifrelimab
An anti-CTLA-4 monoclonal antibody.
Sponsors
Agenus Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Written informed consent. 2. ≥18 years of age. 3. Histological or cytological diagnosis of solid cancer or lymphoma that is considered incurable and without therapies with established benefit. Biopsy is not necessary for participants with known prior diagnosis, and clinical or radiographic evidence of recurrence. For Phase 2 only: Participants who experienced documented disease progression during treatment with an approved or investigational PD-1/PD-L1 inhibitor as their most recent therapy (2-6 weeks prior to first dose of study drug). This cohort includes participants with histological diagnoses of hepatocellular carcinoma (HCC) (not including atypical histology such as cholangiocarcinoma mix or fibrolamellar hepatocellular carcinoma) who experienced documented disease progression during treatment with an approved or investigational PD-1/PD-L1 inhibitor as their most recent therapy (2-6 weeks prior to first dose of study drug). 4. Eastern Cooperative Oncology Group (ECOG) score of 0 or 1. 5. Participants in Phase 2 with HCC should have a Child-Pugh score of A or B7 with no encephalopathy or ascites. 6. Life expectancy ≥12 weeks. 7. Adequate cardiac function (New York Heart Association \[NYHA\] class ≤II). 8. Adequate organ function, defined as absolute neutrophil count (ANC) ≥1,500×10\^6/liter (L), absolute lymphocyte count ≥500/cubic millimeters (mm\^3), hemoglobin ≥8.0 grams/deciliter (g/dL), and platelet count ≥100,000×10\^6/mm\^3 without blood growth factors or without transfusions within 1 week of first dose. For participants in Phase 2 with HCC: Platelet count ≥60×10\^6/mm\^3 and ANC ≥1,000×10\^6/L are acceptable provided that the principal investigator assesses these abnormalities as due to liver disease. 9. Adequate liver function, defined as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5× institutional upper limit of normal (ULN), and bilirubin ≤1.5 milligrams/deciliter (mg/dL) × ULN. For participants in Phase 2 with HCC: AST and ALT ≤5 × ULN, bilirubin ≤2 mg/dL × ULN, and albumin ≥2.8 mg/dL. 10. Adequate renal function, defined as estimated creatinine clearance ≥50 milliliters/minute according to Cockcroft-Gault formula, or measured 24-hour creatinine clearance (or local institutional standard method). 11. Adequate coagulation defined by international normalized ratio (INR) or prothrombin time (PT) ≤1.5× ULN (unless the participant is receiving anticoagulant therapy); and activated partial thromboplastin time ≤1.5× ULN (unless the participant is receiving anticoagulant therapy). Participants in Phase 2 with HCC can have an INR ≤2.3× ULN. Note: Participants in Phase 2 with HCC and on anticoagulant treatment would have an assigned value of 1 point when scoring PT/INR so the overall Child-Pugh score is not adversely affected. 12. Female participants of childbearing potential and fertile male participants must agree to use adequate contraception or abstain from sexual activity from the time of consent through 90 days after the end of study drug. Adequate contraception includes condoms with contraceptive foam; oral, implantable, or injectable contraceptives; contraceptive patch; intrauterine device; diaphragm with spermicidal gel; or a sexual partner who is surgically sterilized or postmenopausal. Note: Abstinence is acceptable if this is the established and preferred contraception for the participant. 13. In the expansion phase, all participants must provide a sufficient and adequate formalin-fixed paraffin embedded (FFPE) tumor tissue sample preferably collected after progression on the last therapy and/or collected at screening, if clinically feasible. If a recent biopsy is not available, an archival FFPE sample should be provided from a site not previously irradiated. If no tumor tissue is available, a fresh biopsy will be required if clinically feasible.
Exclusion criteria
1. Other malignancies treated within the last 5 years, except in situ cervix carcinoma or non-melanoma skin cancer. 2. Other form(s) of antineoplastic therapy anticipated during the period of the study. 3. Previous severe hypersensitivity reaction to another fully human monoclonal antibody or severe reaction to immuno-oncology agents, such as colitis or pneumonitis requiring treatment with steroids. 4. History of interstitial lung disease. 5. Primary or secondary immunodeficiency, including immunosuppressive disease, autoimmune disease (including autoimmune endocrinopathies), or usage of immunosuppressive medications. Note: Participants with diabetes type 1, vitiligo, psoriasis, hypo-, or hyperthyroid disease not requiring immunosuppressive treatment are eligible. Participants with Type 2 diabetes mellitus are allowed. 6. Participants with a known history of human immunodeficiency virus 1 and 2, human T lymphotropic virus 1. Participants in Phase 2 with HCC: Participants with active hepatitis B infection who are receiving effective antiviral therapy are permitted. Participants with active hepatitis C infection are allowed (antiviral therapy not required). 7. Administration of anticancer medications or investigational drugs within the following intervals before the first administration of study drug: a. ≤14 days for chemotherapy, targeted small molecule therapy, or radiation therapy. Participants must also not have had radiation pneumonitis as a result of treatment and cannot participate in the study if they are on chronic corticosteroids for radiation pneumonitis. A 1-week washout is permitted for palliative radiation to non-central nervous system (CNS) disease, with medical monitor approval. Note: Bisphosphonates and denosumab are permitted medications. b. ≤14 days for prior immunotherapy. Participants in the dose escalation cohorts are excluded if they have received prior checkpoint inhibitors, costimulatory agonists, or immune modulating therapy except as described below. Once a dose level is determined to be safe by the safety review committee, participants will be allowed to enroll in dose-level expansion cohorts if they have received other non-CTLA-4 targeting immunotherapies. c. Participants enrolling in Phase 2 must have cancer that has progressed after prior treatment with an approved or investigational PD-1/PD-L1 inhibitor as their most recent therapy (2-6 weeks prior to first dose of study drug). The minimum requirement of 2 weeks (14 days) from prior anti-PD-1/PD-L1 therapy is to allow resolution of any lower-grade (≤2) adverse events observed with the therapy. If the investigator feels the participant has tolerated prior anti-PD-1/PD-L1 therapy well, then treatment with study agent may begin sooner. d. ≤7 days for prior corticosteroid treatment, with the following exceptions: * Use of an inhaled or topical corticosteroid is permitted. * Corticosteroid premedication for radiographic imaging for dye allergies is permitted. * Use of physiologic corticosteroid replacement therapy may be approved after consultation with the medical monitor. e. ≤21 days for prior monoclonal antibody used for anticancer therapy, with the exception of denosumab. This does not apply to participants being enrolled in Phase 2, who have received a PD-1/PD-L1 inhibitor as their most recent therapy (2-6 weeks prior to first dose of study drug; see above). f. ≤7 days for immunosuppressive-based treatment for any reason, with the exceptions noted above for prior corticosteroid treatment (exclusion criterion d). g. ≤21 days or 5 half-lives before first dose of study treatment for all other investigational study drugs or devices. For investigational agents with long half- lives (for example, \>5 days), enrollment before the fifth half-life requires medical monitor approval. h. For participants in Phase 2 with HCC \<6 weeks for prior locoregional therapy to the liver, for example, transcatheter chemoembolization, radiation, surgery, or radioembolization. 8. Has not recovered to grade ≤1 from toxic effects of prior therapy and/or complications from prior surgical intervention before starting therapy. Note: Participants with grade ≤2 neuropathy and alopecia are an exception and may enroll. 9. Uncontrolled infection or other serious medical illnesses. 10. History or presence of an abnormal electrocardiogram that, in the investigator's opinion, is clinically meaningful. 11. Any medical conditions that, in the opinion of the investigator, would preclude use of AGEN1884, including AGEN1884 hypersensitivity. 12. Women who are pregnant or breastfeeding. 13. Concurrent participation in other investigational drug trials. 14. Has a CNS tumor, metastasis(es), and/or carcinomatous meningitis identified either on the baseline brain imaging obtained during the screening period or identified prior to consent. Note: Participants with history of brain metastases that have been treated may participate provided they show evidence of stable supra-tentorial lesions are obtained after treatment to the brain metastases. These imaging scans should both be obtained ≥4 weeks apart). In addition, any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have returned to baseline or resolved. For individuals who received steroids as part of brain metastases treatment, steroids must be discontinued ≥7 days prior to first dose of study drug. 15. For participants in Phase 2 with HCC, the following exclusions also apply: 1. Recent encephalopathy episodes in the last 6 months. 2. Recent (within the last 6 months) gastro-esophageal varices bleeding. 3. Participant whose tumors have cardiac involvement, as determined by imaging.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) of Zalifrelimab | Up to 28 days | A DLT was defined as a Grade ≥3 adverse drug reaction (ADR), according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5, occurring in the DLT evaluation period (28 days after the initial administration of zalifrelimab). An ADR was defined as all noxious and unintended responses to a medicinal product, related to any dose. |
| Phase 1 and Phase 2: Number of Participants Experiencing Any Treatment-related Adverse Events | Up to 6 years | An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that did not necessarily have a causal relationship with this treatment. A treatment-related AE was one in which a causal relationship between the medicinal product and the AE was at least a reasonable possibility and could not be ruled out. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section. |
| Phase 1: Maximum Drug Concentration (Cmax) of Zalifrelimab | Day 1 of Cycle 1 (21 days/cycle) | Blood samples were collected at designated timepoints to characterize Cmax of serum zalifrelimab following IV infusion in participants with metastatic or locally advanced solid tumors. Data reported as micrograms/milliliter (ug/mL). |
| Phase 1: Area Under the Drug Concentration-time Curve From 0 to 21 Days (AUC0-21d) of Zalifrelimab | Day 1 of Cycle 1 (21 days/cycle) | Blood samples were collected at designated timepoints to characterize AUC0-21d of serum zalifrelimab following IV infusion in participants with metastatic or locally advanced solid tumors. Data reported as hour times ug/mL (hour\*ug/mL). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: PFS | Up to 6 years | PFS was defined as the interval from the date of first dose of investigational agent until the earliest date of PD, as determined by independent endpoint review committee assessment of objective radiographic disease assessments per RECIST v1.1, or death due to any cause if occurring sooner than progression. |
| Phase 1 and Phase 2: Objective Response Rate (ORR) | Up to 6 years | ORR was defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) as determined by radiographic disease assessments per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). BOR was defined as the best response recorded from the start of treatment until disease progression/recurrence; any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 millimeters. CR was defined as disappearance of all target lesions, and PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Phase 2: OS | Up to 6 years | OS was defined as the interval from the date of first dose of investigational agent until the date of death. For participants who did not die, OS was censored at last contact date. |
| Phase 1: Overall Survival (OS) | Up to 6 years | OS was defined as the interval from the date of first dose of investigational agent until the date of death. For participants who did not die, OS was censored at last contact date. |
| Phase 1 and Phase 2: Disease Control Rate (DCR) | Up to 6 years | DCR was defined as the percentage of participants who had a confirmed response (CR or PR) or stable disease (SD) without progressive disease (PD). SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that is the smallest on study). |
| Phase 1 and Phase 2: Duration of Response (DOR) | Up to 6 years | DOR was defined as the interval from which the date measurement criteria were met for CR or PR (whichever was first recorded) until the earliest date of disease progression, as determined by investigator assessment of objective radiographic disease assessments per RECIST v1.1, or death due to any cause, if occurring sooner than progression. |
| Phase 1: Progression-free Survival (PFS) | Up to 6 years | PFS was defined as the interval from the date of first dose of investigational agent until the earliest date of PD, as determined by independent endpoint review committee assessment of objective radiographic disease assessments per RECIST v1.1, or death due to any cause if occurring sooner than progression. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1: Zalifrelimab Dose 1 Participants received zalifrelimab (0.1 mg/kg) IV Q3W. | 5 |
| Phase 1: Zalifrelimab Dose 2 Participants received zalifrelimab (0.3 mg/kg) IV Q3W. | 3 |
| Phase 1: Zalifrelimab Dose 3 Participants received zalifrelimab (1.0 mg/kg) IV Q3W. | 10 |
| Phase 1: Zalifrelimab Dose 4 Participants received zalifrelimab (3.0 mg/kg) IV Q3W. | 15 |
| Phase 1: Zalifrelimab Dose 5 Participants received zalifrelimab (6.0 mg/kg) IV Q3W. | 5 |
| Phase 2: Zalifrelimab Participants received zalifrelimab (1.0 mg/kg) IV Q3W. | 51 |
| Total | 89 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Phase 1 | Death | 2 | 1 | 6 | 6 | 3 | 0 |
| Phase 1 | Withdrawal by Subject | 2 | 2 | 4 | 8 | 1 | 0 |
| Phase 2 | Administrative Study Closure | 0 | 0 | 0 | 0 | 0 | 2 |
| Phase 2 | Death | 0 | 0 | 0 | 0 | 0 | 26 |
| Phase 2 | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 1 |
| Phase 2 | Participant Transferred to Another Site | 0 | 0 | 0 | 0 | 0 | 1 |
| Phase 2 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 13 |
Baseline characteristics
| Characteristic | Phase 1: Zalifrelimab Dose 1 | Phase 1: Zalifrelimab Dose 2 | Phase 1: Zalifrelimab Dose 3 | Phase 1: Zalifrelimab Dose 4 | Phase 1: Zalifrelimab Dose 5 | Phase 2: Zalifrelimab | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 4 Participants | 8 Participants | 0 Participants | 21 Participants | 34 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 2 Participants | 6 Participants | 7 Participants | 5 Participants | 30 Participants | 55 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 3 Participants | 4 Participants | 0 Participants | 5 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 2 Participants | 7 Participants | 11 Participants | 5 Participants | 44 Participants | 73 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 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 | 1 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 5 Participants | 9 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 5 Participants | 8 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 | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 4 Participants | 3 Participants | 9 Participants | 9 Participants | 5 Participants | 39 Participants | 69 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 7 Participants | 8 Participants | 3 Participants | 19 Participants | 41 Participants |
| Sex: Female, Male Male | 3 Participants | 1 Participants | 3 Participants | 7 Participants | 2 Participants | 32 Participants | 48 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 | 2 / 5 | 1 / 3 | 6 / 10 | 6 / 15 | 3 / 5 | 26 / 51 |
| other Total, other adverse events | 5 / 5 | 3 / 3 | 10 / 10 | 15 / 15 | 5 / 5 | 48 / 51 |
| serious Total, serious adverse events | 2 / 5 | 2 / 3 | 5 / 10 | 9 / 15 | 3 / 5 | 23 / 51 |
Outcome results
Primary
Phase 1 and Phase 2: Number of Participants Experiencing Any Treatment-related Adverse Events
An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that did not necessarily have a causal relationship with this treatment. A treatment-related AE was one in which a causal relationship between the medicinal product and the AE was at least a reasonable possibility and could not be ruled out. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.
Time frame: Up to 6 years
Population: Safety Analysis Set: all participants who received at least 1 dose of zalifrelimab.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1: Zalifrelimab Dose 1 | Phase 1 and Phase 2: Number of Participants Experiencing Any Treatment-related Adverse Events | 3 Participants |
| Phase 1: Zalifrelimab Dose 2 | Phase 1 and Phase 2: Number of Participants Experiencing Any Treatment-related Adverse Events | 2 Participants |
| Phase 1: Zalifrelimab Dose 3 | Phase 1 and Phase 2: Number of Participants Experiencing Any Treatment-related Adverse Events | 6 Participants |
| Phase 1: Zalifrelimab Dose 4 | Phase 1 and Phase 2: Number of Participants Experiencing Any Treatment-related Adverse Events | 12 Participants |
| Phase 1: Zalifrelimab Dose 5 | Phase 1 and Phase 2: Number of Participants Experiencing Any Treatment-related Adverse Events | 4 Participants |
| Phase 2: Zalifrelimab | Phase 1 and Phase 2: Number of Participants Experiencing Any Treatment-related Adverse Events | 31 Participants |
Primary
Phase 1: Area Under the Drug Concentration-time Curve From 0 to 21 Days (AUC0-21d) of Zalifrelimab
Blood samples were collected at designated timepoints to characterize AUC0-21d of serum zalifrelimab following IV infusion in participants with metastatic or locally advanced solid tumors. Data reported as hour times ug/mL (hour\*ug/mL).
Time frame: Day 1 of Cycle 1 (21 days/cycle)
Population: Pharmacokinetics Analysis Set: all participants who received at least 1 dose of zalifrelimab. As pre-specified, data were collected and are reported for Phase 1 only.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Phase 1: Zalifrelimab Dose 1 | Phase 1: Area Under the Drug Concentration-time Curve From 0 to 21 Days (AUC0-21d) of Zalifrelimab | 317 hour*ug/mL | Standard Error 51.897 |
| Phase 1: Zalifrelimab Dose 2 | Phase 1: Area Under the Drug Concentration-time Curve From 0 to 21 Days (AUC0-21d) of Zalifrelimab | 1522 hour*ug/mL | Standard Error 246.42 |
| Phase 1: Zalifrelimab Dose 3 | Phase 1: Area Under the Drug Concentration-time Curve From 0 to 21 Days (AUC0-21d) of Zalifrelimab | 3915 hour*ug/mL | Standard Error 964.89 |
| Phase 1: Zalifrelimab Dose 4 | Phase 1: Area Under the Drug Concentration-time Curve From 0 to 21 Days (AUC0-21d) of Zalifrelimab | 11390 hour*ug/mL | Standard Error 964.89 |
| Phase 1: Zalifrelimab Dose 5 | Phase 1: Area Under the Drug Concentration-time Curve From 0 to 21 Days (AUC0-21d) of Zalifrelimab | 18803 hour*ug/mL | Standard Error 2370.77 |
Primary
Phase 1: Maximum Drug Concentration (Cmax) of Zalifrelimab
Blood samples were collected at designated timepoints to characterize Cmax of serum zalifrelimab following IV infusion in participants with metastatic or locally advanced solid tumors. Data reported as micrograms/milliliter (ug/mL).
Time frame: Day 1 of Cycle 1 (21 days/cycle)
Population: Pharmacokinetics Analysis Set: all participants who received at least 1 dose of zalifrelimab. As pre-specified, data were collected and are reported for Phase 1 only.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Phase 1: Zalifrelimab Dose 1 | Phase 1: Maximum Drug Concentration (Cmax) of Zalifrelimab | 1.95 ug/mL | Standard Error 0.30946 |
| Phase 1: Zalifrelimab Dose 2 | Phase 1: Maximum Drug Concentration (Cmax) of Zalifrelimab | 7.15 ug/mL | Standard Error 1.3635 |
| Phase 1: Zalifrelimab Dose 3 | Phase 1: Maximum Drug Concentration (Cmax) of Zalifrelimab | 23.1 ug/mL | Standard Error 1.2891 |
| Phase 1: Zalifrelimab Dose 4 | Phase 1: Maximum Drug Concentration (Cmax) of Zalifrelimab | 63.5 ug/mL | Standard Error 9.4314 |
| Phase 1: Zalifrelimab Dose 5 | Phase 1: Maximum Drug Concentration (Cmax) of Zalifrelimab | 120 ug/mL | Standard Error 18.075 |
Primary
Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) of Zalifrelimab
A DLT was defined as a Grade ≥3 adverse drug reaction (ADR), according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5, occurring in the DLT evaluation period (28 days after the initial administration of zalifrelimab). An ADR was defined as all noxious and unintended responses to a medicinal product, related to any dose.
Time frame: Up to 28 days
Population: DLT Evaluable Analysis Set: all participants within the dose escalation (Phase 1) cohorts who received ≥2 doses of zalifrelimab at their assigned dose level and completed the DLT evaluation period of 28 days, or all participants within the dose escalation cohort who received ≥1 dose of zalifrelimab and experienced a DLT. As pre-specified, data were collected and are reported for Phase 1 only.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1: Zalifrelimab Dose 1 | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) of Zalifrelimab | 0 Participants |
| Phase 1: Zalifrelimab Dose 2 | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) of Zalifrelimab | 0 Participants |
| Phase 1: Zalifrelimab Dose 3 | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) of Zalifrelimab | 0 Participants |
| Phase 1: Zalifrelimab Dose 4 | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) of Zalifrelimab | 0 Participants |
| Phase 1: Zalifrelimab Dose 5 | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) of Zalifrelimab | 0 Participants |
Secondary
Phase 1 and Phase 2: Disease Control Rate (DCR)
DCR was defined as the percentage of participants who had a confirmed response (CR or PR) or stable disease (SD) without progressive disease (PD). SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that is the smallest on study).
Time frame: Up to 6 years
Population: Safety Analysis Set: all participants who received at least 1 dose of zalifrelimab. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Zalifrelimab Dose 1 | Phase 1 and Phase 2: Disease Control Rate (DCR) | 20.0 percentage of participants |
| Phase 1: Zalifrelimab Dose 2 | Phase 1 and Phase 2: Disease Control Rate (DCR) | 33.3 percentage of participants |
| Phase 1: Zalifrelimab Dose 3 | Phase 1 and Phase 2: Disease Control Rate (DCR) | 0 percentage of participants |
| Phase 1: Zalifrelimab Dose 4 | Phase 1 and Phase 2: Disease Control Rate (DCR) | 6.7 percentage of participants |
| Phase 1: Zalifrelimab Dose 5 | Phase 1 and Phase 2: Disease Control Rate (DCR) | 0 percentage of participants |
| Phase 2: Zalifrelimab | Phase 1 and Phase 2: Disease Control Rate (DCR) | 37.3 percentage of participants |
Secondary
Phase 1 and Phase 2: Duration of Response (DOR)
DOR was defined as the interval from which the date measurement criteria were met for CR or PR (whichever was first recorded) until the earliest date of disease progression, as determined by investigator assessment of objective radiographic disease assessments per RECIST v1.1, or death due to any cause, if occurring sooner than progression.
Time frame: Up to 6 years
Population: Safety Analysis Set: all participants who received at least 1 dose of zalifrelimab. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Zalifrelimab Dose 1 | Phase 1 and Phase 2: Duration of Response (DOR) | NA weeks |
| Phase 2: Zalifrelimab | Phase 1 and Phase 2: Duration of Response (DOR) | NA weeks |
Secondary
Phase 1 and Phase 2: Objective Response Rate (ORR)
ORR was defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) as determined by radiographic disease assessments per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). BOR was defined as the best response recorded from the start of treatment until disease progression/recurrence; any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 millimeters. CR was defined as disappearance of all target lesions, and PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Up to 6 years
Population: Safety Analysis Set: all participants who received at least 1 dose of zalifrelimab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Zalifrelimab Dose 1 | Phase 1 and Phase 2: Objective Response Rate (ORR) | 20.0 percentage of participants |
| Phase 1: Zalifrelimab Dose 2 | Phase 1 and Phase 2: Objective Response Rate (ORR) | 0 percentage of participants |
| Phase 1: Zalifrelimab Dose 3 | Phase 1 and Phase 2: Objective Response Rate (ORR) | 0 percentage of participants |
| Phase 1: Zalifrelimab Dose 4 | Phase 1 and Phase 2: Objective Response Rate (ORR) | 0 percentage of participants |
| Phase 1: Zalifrelimab Dose 5 | Phase 1 and Phase 2: Objective Response Rate (ORR) | 0 percentage of participants |
| Phase 2: Zalifrelimab | Phase 1 and Phase 2: Objective Response Rate (ORR) | 5.9 percentage of participants |
Secondary
Phase 1: Overall Survival (OS)
OS was defined as the interval from the date of first dose of investigational agent until the date of death. For participants who did not die, OS was censored at last contact date.
Time frame: Up to 6 years
Population: Safety Analysis Set: all participants who received at least 1 dose of zalifrelimab. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure in Phase 1.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Zalifrelimab Dose 1 | Phase 1: Overall Survival (OS) | NA weeks |
| Phase 1: Zalifrelimab Dose 2 | Phase 1: Overall Survival (OS) | 71.143 weeks |
| Phase 1: Zalifrelimab Dose 3 | Phase 1: Overall Survival (OS) | 20.429 weeks |
| Phase 1: Zalifrelimab Dose 4 | Phase 1: Overall Survival (OS) | 70.571 weeks |
| Phase 1: Zalifrelimab Dose 5 | Phase 1: Overall Survival (OS) | 15.000 weeks |
Secondary
Phase 1: Progression-free Survival (PFS)
PFS was defined as the interval from the date of first dose of investigational agent until the earliest date of PD, as determined by independent endpoint review committee assessment of objective radiographic disease assessments per RECIST v1.1, or death due to any cause if occurring sooner than progression.
Time frame: Up to 6 years
Population: Safety Analysis Set: all participants who received at least 1 dose of zalifrelimab. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure in Phase 1.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Zalifrelimab Dose 1 | Phase 1: Progression-free Survival (PFS) | NA weeks |
| Phase 1: Zalifrelimab Dose 2 | Phase 1: Progression-free Survival (PFS) | 11.000 weeks |
| Phase 1: Zalifrelimab Dose 3 | Phase 1: Progression-free Survival (PFS) | 10.429 weeks |
| Phase 1: Zalifrelimab Dose 4 | Phase 1: Progression-free Survival (PFS) | 11.143 weeks |
| Phase 1: Zalifrelimab Dose 5 | Phase 1: Progression-free Survival (PFS) | 5.714 weeks |
Secondary
Phase 2: OS
OS was defined as the interval from the date of first dose of investigational agent until the date of death. For participants who did not die, OS was censored at last contact date.
Time frame: Up to 6 years
Population: Safety Analysis Set: all participants who received at least 1 dose of zalifrelimab.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Zalifrelimab Dose 1 | Phase 2: OS | 16.8 months |
Secondary
Phase 2: PFS
PFS was defined as the interval from the date of first dose of investigational agent until the earliest date of PD, as determined by independent endpoint review committee assessment of objective radiographic disease assessments per RECIST v1.1, or death due to any cause if occurring sooner than progression.
Time frame: Up to 6 years
Population: Safety Analysis Set: all participants who received at least 1 dose of zalifrelimab.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Zalifrelimab Dose 1 | Phase 2: PFS | 2.0 months |