Melanoma (Skin), Cutaneous Melanoma, Adult Disease, Advanced Solid Tumor, Metastatic Melanoma
Conditions
Keywords
IL-2, ANV419, Cancer, Melanoma, OMNIA, Cutaneous, Metastatic, Anti-PD1
Brief summary
The purpose of this study is to evaluate the efficacy and safety of ANV419 monotherapy or the combination of ANV419 with anti-PD1 antibody or with anti-CTLA4 antibody in adult participants with advanced (unresectable or metastatic) cutaneous melanoma. The study has 3 parts. Part 1 to evaluate ANV419 in monotherapy and Parts 2 and 3 to evaluate ANV419 in combination with anti-PD1 antibody or anti-CTLA4 antibody. Parts 2 and 3 were not initiated, as the prespecified efficacy criteria to graduate to Part 2 were not met at the interim analysis of Part 1.
Detailed description
The purpose of this multi-site, open-label, randomized, parallel arm, Phase 1/2 adaptive study is to evaluate the efficacy and safety of ANV419 as a monotherapy and in combination with anti-PD1 antibody or anti-CTLA4 antibody in patients aged 18 years or older with advanced Cutaneous Melanoma who have previously been treated with an anti-PD-1/anti-PD-L1 antibody.
Interventions
DRUGANV419
ANV419 administered by intravenous (IV) infusion
Sponsors
Anaveon AG
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Must provide written informed consent for the study; * Must be able to comply with the Protocol as judged by the Investigator; * Are ≥18 years of age on day of signing informed consent; * Have histologically confirmed Stage 3 (unresectable) or Stage 4 (metastatic) CM, as per the American Joint Committee on Cancer staging system, eighth edition; * Have documented radiological progression on prior systemic therapy; * Have previously received anti-PD-1/L1 as monotherapy or in combination. A maximum of 2 prior lines of systemic therapy is allowed for BRAF wild-type disease and a maximum of 3 prior lines of systemic therapy is allowed for BRAFV600 positive disease; * Have measurable disease based on RECIST; * Have a performance status of 0 or 1 on the ECOG Performance Status; * Have adequate organ functions as defined per protocol; * Female patients of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative (urine or serum) pregnancy test within 72 hours prior to study Day 1. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required and must be negative for the patient to be eligible; * Female patients who are not postmenopausal, and who have not undergone surgical sterilization, must agree to use highly effective methods of contraception during the treatment period and for 6 months after the last dose of study drug. They must also agree not to donate eggs (ova, oocytes) during the same timeframe; and * Male patients with partners of childbearing potential must agree to use highly effective methods of contraception and barrier contraception (condom) during the treatment period and for 6 months after the last dose of study drug. They must also agree not to donate sperm during the same timeframe.
Exclusion criteria
* Have received investigational agent (including investigational device) within 4 weeks or an interval of 5 half-lives of the respective investigational agent prior to study Day 1, whichever is longer, with the exclusion of an anti-PD-1/anti-PD-L1 antibody given as either a single agent or non-CTLA-4 antibody containing combination (eg, anti-lymphocyte-activation gene 3 antibody); * Have a known hypersensitivity to ANV419 or to any of the excipients, such as sucrose, histidine or polysorbate 80. For combination arms only: Have hypersensitivity to pembrolizumab or ipilimumab or any of their excipients; * For combination arms only: Have previously discontinued ipilimumab, pembrolizumab or any other PD-1/PD-L1 inhibitors due to unacceptable drug-related toxicity (defined as toxicities that required second line immunosuppression, ie, not controlled by steroids alone); * Have an LDH level of ≥2 × upper limit of normal; * Have not recovered (ie, ≤Grade 1 or at baseline with the exception of alopecia or fatigue \[up to Grade 2 allowed\]) from AEs resulting from prior immunotherapies. Patients who have autoimmune AEs controlled by replacement therapy (ie, hypothyroidism) due to previous treatment are eligible provided replacement therapy has been initiated and toxicity has returned to Grade 1; * Have not recovered (ie, ≤Grade 1 or at baseline) from toxicities due to a previously administered prior chemotherapy, targeted small molecule therapy, or radiation therapy; Note: If the patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study drug. Major surgery is defined as any surgery requiring entrance into a body cavity (eg, chest, abdomen, or brain), organ removal, normal anatomy alteration, or joint replacement. Minor surgery is defined as any surgery in which skin, mucosa, or connective tissue sections are altered (eg, biopsy, cataract, endoscopic procedures, etc). * Have been diagnosed with uveal/ocular or mucosal melanoma; * Have a known additional malignancy (including all in-situ carcinoma) that is progressing or required active treatment within ≤2 years prior to enrollment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that have undergone potentially curative therapy or in situ cervical cancer or patients who completed cancer-directed therapy and have no evidence of disease; * Have active central nervous system metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to study Day 1 and any neurologic symptoms have returned to baseline or have been stable for at least 7 days), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to study drug. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability; * Have a diagnosis of immunodeficiency or is receiving immunosuppressive therapy within 7 days prior to study Day 1; * Are receiving systemic steroid \>10 mg of prednisone daily or equivalent or any other immunosuppressive medication at any dose level. Local steroid therapies (eg, otic, ophthalmic, intra-articular, or inhaled medications) are acceptable; * Have an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) is not considered a form of systemic treatment; * Have evidence of active, non-infectious pneumonitis; * Have active (measurable) and uncontrolled (unresponsive to current therapy) infectious disease (bacterial, fungal, viral, or protozoic); * Have a history of an acute coronary event (eg, myocardial infarction) within 3 months prior to study Day 1, uncontrolled and symptomatic coronary artery disease or congestive heart failure New York Heart Association Class III/IV; * Have an average QTcF interval \>470 msec at Screening; * Have a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or it is not in the best interest of the patient to participate, in the opinion of the treating Investigator; * Have known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study; * Are pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the Screening Visit through 6 months after the last dose of study drug; * Are known to be human immunodeficiency virus (HIV) positive (or tests positive for HIV 1 or 2 at Screening), unless the following criteria are met: CD4+ lymphocyte count \>350 µL; Had no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections within the past 12 months; Have been on established anti-retroviral therapy for at least 4 weeks; and Have an HIV viral load of \<400 copies/mL prior to study Day 1. Note: Patients on strong cytochrome P450 (CYP)3A4 inhibitors or strong CYP3A4 inducers must be switched to an alternate effective anti-retroviral therapy regimen prior to study treatment or are excluded if regimen prior to study Day 1 cannot be altered. * Have uncontrolled hepatitis B infection or hepatitis C infection; or Note: Patients with hepatitis B (positive hepatitis B surface antigen) who have controlled infection (serum hepatitis B virus DNA by polymerase chain reaction that is below the limit of detection and receiving anti-viral therapy for hepatitis B) are permitted. Patients with controlled infections must undergo periodic monitoring of hepatitis B virus DNA. Note: Patients with hepatitis C (positive hepatitis C virus antibody) who have controlled infection (undetectable hepatitis C virus RNA by polymerase chain reaction either spontaneously or in response to a successful prior course of anti-hepatitis C virus therapy) are permitted. * Have received a live vaccine within 30 days of study Day 1; Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines (eg, Flu-Mist®) are live attenuated vaccines, and are not allowed. * For combination arms only: Have received solid organ or hematopoietic stem cell transplant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Monotherapy Dose Expansion: Objective Response Rate (ORR) as Defined by RECIST v1.1 | Day 1 up to 12 months | Proportion of participants with a complete response (CR) or partial response (PR) to treatment as defined by RECIST v1.1 (ORR = CR + PR) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Monotherapy Dose Expansion: Disease Control Rate (DCR) According to RECIST v1.1 | Day 1 up to 12 months | Percentage of participants who have achieved Complete Response (CR), Partial Response (PR) and Stable Disease (SD). |
| Monotherapy Dose Expansion: Progression-free Survival (PFS) According to RECIST v1.1 | Day 1 up to 12 months | Length of time participants lived with the disease without progressing (PD) |
| Monotherapy Dose Expansion: Overall Survival (OS) Rate | Day 1 up to 6 months | Proportion of participants who are alive at 6 months. This is an estimation based on Kaplan-Meier method. |
| Monotherapy Dose Expansion: Duration of Response (DOR) According to RECIST v1.1 | Day 1 up to 12 months | Time from first time measurement criteria are met for complete response (CR) or (PR) until the progressive disease or death. |
| Monotherapy Dose Expansion: Severity of TEAEs | Day 1 through study completion, an average of 3.7 months and a maximum of 14 months. | Number of participants with TEAEs Grade 3 or more. |
| Monotherapy Dose Expansion: Prevalence of Specific Anti-ANV419 Antibodies (ADA) in Blood | Day 1 through study completion, an average of 3.7 months | Number of patients with positive ADA at baseline and end of study. |
| Monotherapy Dose Expansion: Frequency of Treatment-Emergent Adverse Events (TEAEs) | Day 1 through study completion, an average of 3.7 months and a maximum of 14 months. | Number of participants with TEAEs. |
Countries
France, Germany, Italy, Spain, United States
Participant flow
Recruitment details
In line with the protocol, Parts 2 and 3 of the study were not initiated, as the prespecified efficacy criteria to graduate to Part 2 were not met during Part 1. No participants were enrolled in Parts 2 and 3 prior to the close of the study.
Participants by arm
| Arm | Count |
|---|---|
| ANV419 Single Agent, Low Dose ANV419: ANV419 administered by intravenous (IV) infusion | 14 |
| ANV419 Single Agent, High Dose ANV419: ANV419 administered by intravenous (IV) infusion | 15 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Physician Decision | 1 | 2 |
| Overall Study | Progressive disease | 10 | 9 |
| Overall Study | Sponsor decision | 0 | 1 |
| Overall Study | Toxicity and Patient's decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | ANV419 Single Agent, Low Dose | ANV419 Single Agent, High Dose | Total |
|---|---|---|---|
| Age, Continuous | 59.7 years STANDARD_DEVIATION 14.15 | 59.8 years STANDARD_DEVIATION 13.92 | 59.8 years STANDARD_DEVIATION 13.78 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 8 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 7 Participants | 13 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) White | 11 Participants | 12 Participants | 23 Participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Male | 9 Participants | 10 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 14 | 5 / 15 |
| other Total, other adverse events | 14 / 14 | 15 / 15 |
| serious Total, serious adverse events | 10 / 14 | 11 / 15 |
Outcome results
Primary
Monotherapy Dose Expansion: Objective Response Rate (ORR) as Defined by RECIST v1.1
Proportion of participants with a complete response (CR) or partial response (PR) to treatment as defined by RECIST v1.1 (ORR = CR + PR)
Time frame: Day 1 up to 12 months
Population: The efficacy population included patients who receive at least 1 dose of study drug and have at least 1 post-baseline tumor assessment. No patients achieved CR or PR.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ANV419 Single Agent, Low Dose | Monotherapy Dose Expansion: Objective Response Rate (ORR) as Defined by RECIST v1.1 | 0 Participants |
| ANV419 Single Agent, High Dose | Monotherapy Dose Expansion: Objective Response Rate (ORR) as Defined by RECIST v1.1 | 0 Participants |
Secondary
Monotherapy Dose Expansion: Disease Control Rate (DCR) According to RECIST v1.1
Percentage of participants who have achieved Complete Response (CR), Partial Response (PR) and Stable Disease (SD).
Time frame: Day 1 up to 12 months
Population: The efficacy population included patients who receive at least 1 dose of study drug and have at least 1 post-baseline tumor assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ANV419 Single Agent, Low Dose | Monotherapy Dose Expansion: Disease Control Rate (DCR) According to RECIST v1.1 | 5 Participants |
| ANV419 Single Agent, High Dose | Monotherapy Dose Expansion: Disease Control Rate (DCR) According to RECIST v1.1 | 7 Participants |
Secondary
Monotherapy Dose Expansion: Duration of Response (DOR) According to RECIST v1.1
Time from first time measurement criteria are met for complete response (CR) or (PR) until the progressive disease or death.
Time frame: Day 1 up to 12 months
Population: The efficacy population included patients who receive at least 1 dose of study drug and have at least 1 post-baseline tumor assessment. No patients achieved CR or PR so this outcome could not be assessed.
Secondary
Monotherapy Dose Expansion: Frequency of Treatment-Emergent Adverse Events (TEAEs)
Number of participants with TEAEs.
Time frame: Day 1 through study completion, an average of 3.7 months and a maximum of 14 months.
Population: The Safety Population is defined as all patients who receive at least 1 dose (or partial dose) of study drug(s)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ANV419 Single Agent, Low Dose | Monotherapy Dose Expansion: Frequency of Treatment-Emergent Adverse Events (TEAEs) | 14 Participants |
| ANV419 Single Agent, High Dose | Monotherapy Dose Expansion: Frequency of Treatment-Emergent Adverse Events (TEAEs) | 15 Participants |
Secondary
Monotherapy Dose Expansion: Overall Survival (OS) Rate
Proportion of participants who are alive at 6 months. This is an estimation based on Kaplan-Meier method.
Time frame: Day 1 up to 6 months
Population: The Safety Population is defined as all patients who receive at least 1 dose (or partial dose) of study drug(s).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ANV419 Single Agent, Low Dose | Monotherapy Dose Expansion: Overall Survival (OS) Rate | 0.8 Proportion of participants |
| ANV419 Single Agent, High Dose | Monotherapy Dose Expansion: Overall Survival (OS) Rate | 0.8 Proportion of participants |
Secondary
Monotherapy Dose Expansion: Prevalence of Specific Anti-ANV419 Antibodies (ADA) in Blood
Number of patients with positive ADA at baseline and end of study.
Time frame: Day 1 through study completion, an average of 3.7 months
Population: The Immunogenicity Population is defined as all patients who receive at least 1 dose of study drug and have at least 1 evaluable immunogenicity sample.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ANV419 Single Agent, Low Dose | Monotherapy Dose Expansion: Prevalence of Specific Anti-ANV419 Antibodies (ADA) in Blood | Prevalence of ADA positive at Baseline | 5 Participants |
| ANV419 Single Agent, Low Dose | Monotherapy Dose Expansion: Prevalence of Specific Anti-ANV419 Antibodies (ADA) in Blood | Prevalence of ADA positive at End of Study | 12 Participants |
| ANV419 Single Agent, High Dose | Monotherapy Dose Expansion: Prevalence of Specific Anti-ANV419 Antibodies (ADA) in Blood | Prevalence of ADA positive at Baseline | 5 Participants |
| ANV419 Single Agent, High Dose | Monotherapy Dose Expansion: Prevalence of Specific Anti-ANV419 Antibodies (ADA) in Blood | Prevalence of ADA positive at End of Study | 5 Participants |
Secondary
Monotherapy Dose Expansion: Progression-free Survival (PFS) According to RECIST v1.1
Length of time participants lived with the disease without progressing (PD)
Time frame: Day 1 up to 12 months
Population: The safety population is defined as all patients who receive at least 1 dose (or partial dose) of study drug(s).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ANV419 Single Agent, Low Dose | Monotherapy Dose Expansion: Progression-free Survival (PFS) According to RECIST v1.1 | 2.2 months |
| ANV419 Single Agent, High Dose | Monotherapy Dose Expansion: Progression-free Survival (PFS) According to RECIST v1.1 | 2.4 months |
Secondary
Monotherapy Dose Expansion: Severity of TEAEs
Number of participants with TEAEs Grade 3 or more.
Time frame: Day 1 through study completion, an average of 3.7 months and a maximum of 14 months.
Population: The Safety Population is defined as all patients who receive at least 1 dose (or partial dose) of study drug(s)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ANV419 Single Agent, Low Dose | Monotherapy Dose Expansion: Severity of TEAEs | 12 Participants |
| ANV419 Single Agent, High Dose | Monotherapy Dose Expansion: Severity of TEAEs | 13 Participants |