A Study of ASP3082 in Adults With Previously Treated Solid Tumors

A Phase 1 Study of ASP3082 in Participants With Previously Treated Locally Advanced or Metastatic Solid Tumor Malignancies With KRAS G12D Mutation

Genes contain genetic code which tell the body which proteins to make. Many types of cancer are caused by changes, or mutations, in a gene called KRAS. Researchers are looking for ways to stop the actions of abnormal proteins made from the mutated KRAS gene. The so-called G12D mutation in the KRAS gene is common in people with some solid tumors. ASP3082 is a potential new treatment for certain solid tumors in people who have the G12D mutation in their KRAS gene. Before ASP3082 is available as a treatment, the researchers need to understand how it is processed by and acts upon the body. This information will help find a suitable dose and to check for potential medical problems from the treatment. People in this study will be adults with locally advanced, unresectable or metastatic solid tumors with the G12D mutation in their KRAS gene (G12D mutation). Locally advanced means the cancer has spread to nearby tissue. Unresectable means the cancer cannot be removed by surgery. Metastatic means the cancer has spread to other parts of the body. They will have been previously treated with standard therapies or refused to receive those treatments. The main aims of the study are: to check the safety of ASP3082 by itself and together with cetuximab (a common cancer medicine), how well it is tolerated, and to find a suitable dose of ASP3082 by itself and together with cetuximab. This is an open-label study. This means that people in this study and clinic staff will know that they will receive ASP3082. This study will be in 2 parts. In Part 1, different small groups of people will receive lower to higher doses of ASP3082, by itself, or together with cetuximab. Only people with colorectal cancer will receive ASP3082 together with cetuximab. Any medical problems will be recorded at each dose. This is done to find suitable doses of ASP3082 by itself or together with cetuximab to use in Part 2 of the study. The first group will receive the lowest dose of ASP3082. A medical expert panel will check the results from this group and decide if the next group can receive a higher dose of ASP3082. The panel will do this for each group until all groups have received ASP3082 (by itself or together with cetuximab) or until suitable doses have been selected for Part 2. In Part 2, other different small groups of people will receive ASP3082 by itself or together with cetuximab, with the most suitable doses worked out from Part 1. This will help find a more accurate dose of ASP3082 to use in future studies. ASP3082, and cetuximab (if used), will be given through a vein. This is called an infusion. Each treatment cycle is 21 days long. They will continue treatment until: they have medical problems from the treatment they can't tolerate; their cancer gets worse; they start other cancer treatment; they ask to stop treatment; they do not come back for treatment. People will visit the clinic on certain days during their treatment, with extra visits during the first 2 cycles of treatment. During these visits, the study doctors will check for any medical problems from ASP3082 by itself or together with cetuximab. At some visits, other checks will include a medical examination, blood and urine tests and vital signs. Vital signs include temperature, pulse, breathing rate, and blood pressure. (Blood oxygen levels will also be checked for people treated with ASP3082 together with cetuximab.) Tumor samples will be taken during certain visits during treatment and when treatment has finished. People will visit the clinic within 7 days after stopping treatment. The study doctors will check for any medical problems from ASP3082 by itself or together with cetuximab. Other checks will include a medical examination, urine and blood tests and vital signs. After this, people will continue to visit the clinic every 9 weeks. This is to check the condition of their cancer. They will do this until 45 weeks after treatment stopped, or if their cancer is worse, they start other cancer treatment, they ask to stop treatment, or they do not come back for treatment. Also, people may visit the clinic at 30 days and 90 days after stopping treatment. At the 30-day visit, the study doctors will check for any medical problems from ASP3082 by itself or together with cetuximab. People will have their vital signs checked and have some blood tests. At the 90-day visit, the study doctors will check for any medical problems from ASP3082 by itself or together with cetuximab and people will have their vital signs checked.

Participants will receive ASP3082 with dose level(s) selected from dose escalation (part 1) in a 21-day cycle.

Participants with locally advanced or metastatic colorectal cancer will receive ASP3082 or ASP3082 + Cetuximab with dose level(s) selected from dose escalation (part 1) in a 21-day cycle. Cetuximab will be administered weekly.

Participants will receive ASP3082 with dose level selected from dose escalation (Monotherapy part 1) in a 21-day cycle.

A DLT is defined as any event meeting the DLT criteria occurring within 21 days of first dose on Cycle 1 Day 1 (C1D1), excluding toxicities clearly related to disease progression or intercurrent illness.

An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study IP, whether or not considered related to the study investigational product (IP). Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease (new or exacerbated) temporally associated with the use of study IP. This includes events related to the comparator and events related to the (study) procedures.

An SAE is defined as any untoward medical occurrence that, at any dose: Results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, and other medically important events.

The ECOG scale will be used to assess performance status. Grades range from 0 (fully active) to 5 (dead). Negative change scores indicate an improvement. Positive scores indicate a decline in performance.

ORR is defined as the proportion of participants whose best overall response is rated as complete response (CR) or partial response (PR) per RECIST v1.1.

DOR is measured from the time measurement criteria are first met for CR/PR (whichever is first recorded) until the first date of documented radiological disease progression per RECIST v1.1 or death in the absence of progression.

DCR is defined as the proportion of participants whose best overall response is rated as CR, PR or SD based on RECIST v1.1.

Inclusion Criteria: Participant has locally advanced (unresectable) or metastatic solid tumor malignancy with documented Kirsten rat sarcoma viral oncogene homolog [KRAS] G12D mutation and has received prior standard therapy and the investigator does not see any further clinical benefit from continuing such targeted therapy, or is ineligible to receive or has refused standard approved therapies (no limit to the number of prior treatment regimens). For ASP3082 monotherapy escalation cohort, participants with solid tumor malignancies are allowed to be enrolled. For dose expansion cohorts, PDAC patients must have received no more than 2 prior lines of therapy. For ASP3082 +cetuximab cohorts, participants with CRC are allowed to be enrolled. Participant consents to provide tumor specimen in a tissue block or unstained serial slides or a tumor biopsy (core needle biopsy or excision) obtained after the last interventional treatment, but not more than 56 days prior to start of study intervention. Participant also consents to provide a sample for tumor biopsy during the treatment period as indicated in the study protocol. For dose expansion cohorts, if a participant cannot undergo a baseline biopsy procedure, an archival tumor tissue specimen (up to 5 - years prior) is required. (Not applicable for the China safety cohort) Participant has at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. Participant has an ECOG performance status of 0, 1 or 2 for dose escalation, and 0 or 1 for dose expansion. Participant's last dose of prior antineoplastic therapy, including any immunotherapy, was 21 days or 5 half-lives, whichever is shorter, prior to initiation of study intervention administration. Participant has completed any radiotherapy (including stereotactic radiosurgery) at least 14 days prior to the start of study intervention administration. Participants must have recovered from all radiation-related toxicities, not require corticosteroids (NOTE: Physiologic replacement dose of hydrocortisone or its equivalent [defined as up to 30 mg per day of hydrocortisone, 2 mg per day of dexamethasone, or up to 10 mg per day of prednisone] is permitted), and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (<= 2 weeks of radiotherapy) to non-central nervous system disease. Participant's adverse events [AEs] (excluding alopecia) from prior therapy have improved to grade 1 or baseline within 14 days prior to start of study intervention. Participant has adequate organ function as indicated by protocol laboratory value parameters (If a participant has received a recent blood transfusion, the laboratory tests must be obtained >= 14 days after any blood transfusion.). Female participant is not pregnant, confirmed by pregnancy test and medical evaluation by interview, and at least 1 of the following conditions apply: Not a woman of childbearing potential (WOCBP). WOCBP who agrees to follow the contraceptive guidance from the time of informed consent through at least 6 months after study intervention administration. Female participant must agree not to breastfeed starting at screening and throughout the study period and for 6 months after study intervention administration. Female participant must not donate ova starting at first dose of study intervention and throughout the study period and for 6 months after study intervention administration. Male participant with female partner(s) of childbearing potential (including breastfeeding partner) must agree to use contraception throughout the treatment period and for 3 months after study intervention administration. Male participant must not donate sperm during the treatment period and for 3 months after study intervention administration. Male participant with pregnant partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy throughout the study period and for 3 months after study intervention administration. Participant agrees not to participate in another interventional study while receiving study intervention (Participants who are currently in the follow-up period of an interventional clinical trial are allowed). Exclusion Criteria: Participant has received investigational therapy within 21 days or 5 half-lives, whichever is shorter, prior to start of study intervention. Participant has symptomatic or untreated central nervous system (CNS) metastases. Participants with asymptomatic, treated CNS metastases are eligible. Participant has leptomeningeal disease as a manifestation of the current malignancy. Participant has a prior malignancy active (i.e., requiring treatment or intervention) within the previous 2 years, except for local malignancies that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix or breast, which are allowed. Participant has a known or suspected hypersensitivity to ASP3082 or any components of the formulation used. Participant with active hepatitis B (including acute hepatitis B virus [HBV] or chronic HBV) or hepatitis C virus [HCV] (ribonucleic acid [RNA] detected by qualitative assay). HCV RNA testing is not required in participants with negative HCV antibody testing. Participant has a known history of human immunodeficiency virus [HIV] infection. No HIV testing is required unless mandated by a local health authority. Participant has had a myocardial infarction or unstable angina within 6 months prior to the start of study intervention or currently has an uncontrolled illness including, but not limited to symptomatic congestive heart failure, clinically significant cardiac disease, unstable angina pectoris, cardiac arrhythmia, obligate use of a cardiac pacemaker, or long QT syndrome. Participant has a corrected QT interval (single electrocardiogram [ECG]) using Fridericia's formula (QTcF) > 450 milliseconds (msec) (men) or >470 msec (women) during screening. Participant has received prior treatment with a specific KRAS G12D inhibitor/degrader or pan-RAS inhibitor/degrader targeting KRAS G12D. Participants who received prior treatment with a KRAS G12D inhibitor/degrader are eligible for the ASP3082 combination therapy cohort. Participant has an active infection requiring intravenous antibiotics within 14 days prior to study intervention. Participant is expected to require another form of antineoplastic therapy while on study treatment. Participant has any condition which makes the participant unsuitable for study participation (such as psychiatric illness/social situations that would limit compliance with study requirements). Participant has known history of COVID-19 positive polymerase chain reaction (PCR) test within 4 weeks prior to the start of study treatment. Participant has had major surgery within 4 weeks prior to first dose of study intervention. For ASP3082 Combination Therapy for CRC: Prior discontinuation of cetuximab treatment due to toxicity or intolerance of cetuximab. History of interstitial lung disease requiring systemic steroid treatment. Note that a participant with resolved pulmonary infections or radiation pneumonitis is eligible.

Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as compounds terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.

Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.

Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.