Advanced Melanoma, Metastatic Melanoma
Conditions
Keywords
Immune Checkpoint Inhibitor
Brief summary
This is a first-in-human, multi-center, multi-cohort, open-label, phase Ib/II study of XmAb22841 (CTLA-4 X LAG3) administered in combination with XmAb23104 (PD1 X ICOS) in participants with a histologically or cytologically confirmed diagnosis of an advanced/metastatic melanoma. XmAb22841 (CTLA-4 X LAG3) is a bi-specific antibody targeting two different T cell membrane proteins responsible for regulation of T cell activity. It offers potential immunologic and safety advantages over existing therapies. XmAb22841 (CTLA-4 X LAG3) is being evaluated in this clinical study designed to assess the safety, tolerability, PK, and PD of escalating doses of XmAb22841 (CTLA-4 X LAG3) administered in combination with XmAb23104 (PD1 X ICOS) The study will be conducted through the University of California Melanoma Consortium (UCMC).
Detailed description
PRIMARY OBJECTIVES: I. Dose Escalation Phase (Part 1): To estimate the recommended phase 2 dose (RP2D) of XmAb22841 (CTLA-4 X LAG3) in combination XmAb23104 (PD1 X ICOS). II. Dose Expansion Phase (Part 2): To assess clinical response as measured by objective response rate of patients treated with XmAb22841 (CTLA-4 X LAG3) in combination XmAb23104 (PD1 X ICOS). \*\*PHASE 2 Dose Expansion (Part 2) was never initiated\*\*. SECONDARY OBJECTIVES: I. To evaluate the pharmacokinetics (PK) and anti-drug antibody (ADA) immunogenicity of XmAb23104 (PD1 X ICOS) and XmAb22841 (CTLA-4 X LAG3) (Dose Escalation (Part 1) & Dose Expansion (Part 2)). II. To evaluate the clinical efficacy of XmAb23104 (PD1 X ICOS) and XmAb22841 (CTLA-4 X LAG3) (Dose Expansion (Part 2)). \*\*PHASE 2 Dose Expansion (Part 2) was never initiated\*\*. EXPLORATORY OBJECTIVES: I. To identify molecular (genomic, metabolic, and/or proteomic) biomarkers that may be indicative of clinical response/resistance, safety, pharmacodynamic activity, and/or the mechanism of action of XmAb22841 (CTLA-4 X LAG3) administered in combination with XmAb23104 (PD1 X ICOS) (Dose Escalation (Part 1) & Dose Expansion(Part 2)). OUTLINE: Participants were enrolled in the Dose Escalation Phase (Part 1). PHASE 2 Dose Expansion (Part 2) was never initiated. Participants may continue trial therapy until the earlier of radiographic disease progression, withdrawal, unacceptable toxicity, completion of 24 cycles of XmAb23104 (PD1 X ICOS), or other treatment discontinuation due to unacceptable toxicity, participant withdrawal, progressive disease or death. The entire treatment duration of twenty-four 28-day cycles is approximately 2 years. After discontinuing trial therapy, participants will be followed for toxicity, response, and overall survival every 12 weeks for up to 5 years from initiation of study treatment.
Interventions
DRUGXmAb22841
Given intravenously (IV)
DRUGXmAb23104
Given intravenously (IV)
Sponsors
Xencor, Inc.
University of California, San Francisco
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The Phase 2 Dose Expansion (Part 2) portion of the study was never initiated.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Participants must have a histologically or cytologically confirmed advanced/metastatic melanoma by pathology report. Participants with cutaneous, mucosal, acral and unknown primaries will be allowed. 2. Participants must have progressed on either single agent programmed cell death protein 1 (PD1) or combination PD1/ cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibition therapy. 3. Participants are allowed to have up to 4 prior lines of therapy in the metastatic setting. NOTE: Prior BRAF targeted therapies are allowed. Prior exposure to immunotherapeutics is allowed, including LAG-3, PD1, and PD-L1 inhibitors, provided participant did not experience a \>= Grade 3 (CTCAE v5.0) drug-related toxicity on monotherapy with a Expression of lymphocyte activation gene 3 (LAG-3), PD1, or programmed death-ligand 1 (PD-L1) inhibitor. 4. For Dose Escalation Phase, central nervous system (CNS) disease is not required, but it is permitted, provided the following three CNS criteria are met: A. CNS lesions must be asymptomatic and stable, as determined by stability on magnetic resonance imaging (MRI) at least 4 weeks prior to study enrollment. B. Prior radiation treatment to CNS lesions will be allowed; however, the participant must have recovered from prior toxicities as described in Exclusion #2. C. Brain lesions \>= 5 mm are allowed. NOTE: See also exclusion criterion #5 for additional CNS requirements. 5. For Dose Expansion Phase: * Participants in Expansion Arm A must have metastatic melanoma without CNS disease * Participants in Expansion Arm B must have metastatic melanoma with CNS disease, and the following three CNS criteria must be met: A. CNS lesions must be asymptomatic and stable, as determined by stability on MRI at least 4 weeks prior to study enrollment. B. Prior radiation treatment to CNS lesions will be allowed; however, the participant must have recovered from prior toxicities as described in
Exclusion criteria
#2. C. Brain lesions \>= 5 mm are allowed. NOTE: See also exclusion criterion #5 for additional CNS requirements. 6. Participants must have measurable disease according to RECIST 1.1 with the following modification for brain lesions (if brain lesions are present): \- Measurable brain lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as \>= 5 mm. Measurable lesions for all other non-brain sites are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as \>=20 mm (\>=2 cm) by chest x-ray or as \>=10 mm (\>=1 cm) with Computerized tomography (CT) scan, MRI, or calipers by clinical exam. NOTE: MRI brain (or equivalent brain imaging) is required at baseline for all patients to characterize brain disease status. 7. Age \>=18 years. 8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Karnofsky \>60%). 9. Demonstrate adequate organ function as defined below obtained within 14 days prior to the start of study treatment: NOTE: Criteria must be met without packed red blood cell (pRBC) and platelet transfusion within the prior 2 weeks. Participants can be on a stable dose of erythropoietin (\>=approximately 3 months). Bone Marrow: a) Absolute neutrophil count \>=1,500/microliter (mcL) b) Platelets \>=100,000/mcL c) Hemoglobin \>=9 g/dL or \>5.6 mmol/L Renal: d) Serum creatinine or creatinine clearance (CrCl) (measured or calculated per institutional standard) OR for participants with creatinine levels \>1.5 × upper limit of normal (ULN): Glomerular Filtration Rate (GFR) must be assessed, Creatinine \<=1.5 × ULN OR for participants with creatinine levels \>1.5 × ULN: GFR \>30 mL/min/1.73 m\^2 calculated per institutional standard method. Hepatic: e) Total bilirubin (serum) \<=1.5 × ULN, unless elevated due to Gilbert's syndrome and direct bilirubin is within normal limits. f) Aspartate aminotransferase (AST)/ (serum glutamic-oxaloacetic transaminase (SGOT) ) \<=2.5 x ULN or For participants with liver metastasis: \<=5 x ULN g) Alanine aminotransferase (ALT)/(serum glutamic-pyruvic transaminase (SGPT)) \<=2.5 x ULN or For participants with liver metastasis: \<= 5 x ULN Coagulation: h) International Normalized Ratio (INR) or Prothrombin Time (PT) or Activated Partial Thromboplastin Time (aPTT) \<1.5 ULN (unless participant is on therapeutic anticoagulant therapy, in which case the PT/INR or aPTT should be within the range of intended use for the anticoagulant(s)). 10. For HIV-infected participants, participants must have well controlled HIV on anti-retroviral therapy (ART), defined as: a) Participants on ART must have a CD4+ T-cell count \>350 cells/mm3 at time of screening. b) Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 or the lower limit of quantitation (LLOQ) (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks prior to screening. c) Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks prior to initiating the study intervention. d) The combination ART regimen must not contain any antiretroviral medications other than: abacavir, dolutegravir, emtricitabine, lamivudine, raltegravir, rilpivirine, or tenofovir. 11. The effects of XmAb23104 and XmAb22841 on the developing human fetus and nursing infant are unknown. Additionally, it is not known if XmAb23104 and XmAb22841 have transient adverse effects on the composition of sperm. Therefore, participants who enroll in this trial must agree to follow the below contraception requirements. Contraception Requirements for Females: * Female participants should immediately inform the investigator if they become pregnant or suspect pregnancy while participating in the trial. * Female participants of reproductive potential must agree to remain abstinent or use a highly effective method of contraception £ while receiving trial therapy and for 150 days following completion of trial therapy. Women also must not freeze or donate eggs during this same period. Contraception Requirements for Males: * Male participants should immediately inform the investigator if their partner becomes pregnant or suspects pregnancy while they are participating in the trial. * With a female partner of reproductive potential, males must agree to remain abstinent or use a highly effective method of contraception £ while receiving trial therapy and for 150 days following completion of trial therapy. Men also must not donate sperm during this same period. * With a pregnant female partner, males must remain abstinent or use a condom while receiving trial therapy and for 150 days following completion of trial therapy to avoid exposing the embryo/child. * With a lactating female partner, males must remain abstinent or use a condom while receiving trial therapy and for 150 days following completion of trial therapy to avoid exposing the nursing infant. NOTE: A woman is considered NOT to be of reproductive potential (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice), if she meets either of the following two criteria: 1. has reached a postmenopausal state (\>= 12 continuous months of amenorrhea with no identified cause other than menopause) 2. has undergone surgical sterilization (i.e., hysterectomy and/or bilateral oophorectomy for removal of uterus and/or ovaries) NOTE: Sexual abstinence is defined as not engaging in heterosexual intercourse. Sexual abstinence is permitted only if it is the preferred and usual lifestyle of the individual. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not adequate methods of contraception. NOTE: Highly effective methods of birth control include hormonal birth control that is initiated at least 14 days prior to the first dose of trial therapy \[oral, intravaginal, transdermal, implantable, or intrauterine devices (IUDs)\], IUDs (non-hormonal), male vasectomy, or any double-barrier method (combination of male condom and spermicide with either cap, diaphragm, or sponge). 12\. Females of reproductive potential (defined in inclusion criterion #11) must have a negative urine or serum pregnancy test (i.e., human chorionic gonadotropin test) within 72 hours before the first dose of study intervention. NOTE: If a urine pregnancy test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. 13\. Individuals with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. 14\. Participant (or the participant's legally authorized representative if the participant has impaired decision-making capacity) must have the ability to understand and the willingness to sign a written informed consent document. NOTE: The participant/Legally Authorized Representative (LAR) may elect to provide consent for optional participation in future biomedical research (FBR). However, the participant may participate in the main study without participating in the optional FBR.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Treatment- Emergent Adverse Events (Part 1) | Up to 24 months | The number of all treatment-emergent adverse events (AEs) for each dose level and cohort, as determined by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be reported for each cohort in the dose escalation phase. |
| Number of Treatment- Emergent, Immune-Related, Adverse Events (Part 1) | Up to 24 months | The number of all treatment-emergent, immune-related adverse events (irAEs) for each dose level and cohort, as determined by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be reported for each cohort in the dose escalation phase. |
| Number of Participants with Dose Limiting Toxicities (DLT) (Part 1) | Up to 42 days | The DLT evaluation period for the initial cohort of n=3 patients will be 6 weeks after beginning treatment to account for possible delayed DLTs. The number participants experiencing DLTs during the evaluation period will be reported for each cohort in in the dose escalation phase. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean maximum concentration (Cmax) | Up to 25 months | Serum levels of XmAb23104 and XmAb22841 to determine the maximum concentration will be assessed longitudinally beginning on the first day of treatment and individual participant through the safety follow up visit. |
| Overall incidence of anti-XmAb23104 and anti-XmAb22841 antibodies | Up to 25 months | Serum Anti-drug antibodies (ADAs) will be assessed longitudinally beginning on the first day of treatment and individual participant through the safety follow up visit. |
| Median Progression-Free Survival (PFS) (Part 2 only) | Up to 60 months | PFS will be assessed for a period of 5 years from the time of initiation of study treatment, or until progression or death due to any cause, whichever occurs first for participants in Cohorts A & B (dose expansion phase). |
| Objective Response Rate (Part 2) | Up to 24 months | Objective response (defined as a Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 best response of partial response (PR) or CR) will be assessed for each individual participant for a period of 5 years from the time of initiation of study treatment, or until CR/PR is recorded, or progression is observed, whichever occurs first for participants in the dose expansion phase |
| Median Duration of Response (DoR) (Part 2 only) | Up to 60 months | DoR will be assessed from the first date of response (CR or PR per RECIST 1.1) for a period of 5 years from the time of initiation of study treatment, or until the date of progression or death due to any cause, whichever occurs first for participants Cohorts A & B (dose expansion phase). |
| Clinical Benefit Rate (CBR) (Part 2 only) | Up to 60 months | Clinical benefit (defined as a RECIST 1.1 response of stable disease (SD) for \> 6 months, PR, or CR) will be assessed for a period of 5 years from the time of initiation of study treatment, or until SD \> 6 months/CR/PR is recorded, or progression is observed, whichever occurs first for participants in Cohorts A & B (dose expansion phase). |
| CNS response rate (Cohort B Only) | Up to 60 months | CNS response (defined as a RECIST 1.1 CNS best response of PR or CR) will be assessed for a period of 5 years from the time of initiation of study treatment, or until CNS CR/PR is recorded, or CNS progression is observed, whichever occurs first for participants in Cohort B only. |
| Median overall survival (OS) (Part 2 only) | Up to 60 months | OS will be assessed for a period of 5 years from the time of initiation of study treatment, or until death due to any cause, whichever occurs first for participants in Cohorts A & B (dose expansion phase). |
| Area under the curve (AUC) | Up to 24 months | Serum levels of XmAb23104 and XmAb22841 will be assessed longitudinally to determine the AUC beginning on the first day of treatment and individual participant through the safety follow up visit. |
| Minimum concentration (Cmin) | Up to 25 months | Serum levels of XmAb23104 and XmAb22841 to determine the minimum concentration will be assessed longitudinally beginning on the first day of treatment and individual participant through the safety follow up visit. |
Countries
United States
Outcome results
None listed