Locally Advanced or Metastatic Malignant Solid Tumors
Conditions
Keywords
ASP2998, Safety, Tolerability, Pembrolizumab, Enfortumab Vedotin, Carboplatin, Non-small cell lung cancer, Gastroesophageal junction cancer, Breast cancer, Pharmacokinetics, Urothelial carcinoma
Brief summary
Specific proteins found in tumors help the tumors spread and grow. People with solid tumors often have a protein called TROP2 in their tumor. ASP2998 is being developed to attach to TROP2 and then attack the tumor cells in people with solid tumors. ASP2998 will either be given by itself, or given together with one or more of standard cancer treatments pembrolizumab, carboplatin, and enfortumab vedotin. This is an early development study to collect information about ASP2998 in people with solid tumors. In this study ASP2998 will be given to humans for the first time. Early development studies are mostly about safety, but also to find the most suitable dose. Other aims are to check if ASP2998 shows signs of reducing tumor growth, to learn how the body processes ASP2998, and to check if there are changes either in the TROP2 protein or in the immune system. The main aim of the study is to check the safety of ASP2998 when given by itself and given with the standard cancer treatments, and how well it is tolerated. People in this study will be adults with locally advanced, unresectable or metastatic solid tumors. 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. People's cancer came back or became worse after previous treatment or they couldn't receive treatment. Some people who had previously refused treatment may be able to take part. This will depend on which study treatment they receive. People will either have cancer in the bladder lining (urothelial cancer), non-small cell lung cancer (NSCLC), gastric cancer or cancer where the food pipe joins the stomach (gastroesophageal cancer, or GEJ), or certain types of breast cancer. People cannot take part if the cancer cells have spread to the thin tissue covering the brain and spinal cord (leptomeningeal disease), have symptoms of cancer in the brain or nervous system, or need medicines to suppress their immune system. In this study, ASP2998 will be given to humans for the first time. ASP2998 will either be given by itself, or given together with one or more of standard cancer treatments pembrolizumab, carboplatin and enfortumab vedotin. The standard cancer treatment given will depend on which cancer people have. The study will have 2 parts. In Part 1, different small groups of people will receive lower to higher doses of ASP2998 given by itself or together with one or more of the standard cancer treatments. Any medical problems will be recorded for each dose. This is done to find suitable doses of ASP2998 to use in Part 2. In Part 2, other different small groups will receive suitable doses of ASP2998 worked out from Part 1. ASP2998 will either be given by itself or given together with one or more of the standard cancer treatments. This part will also check how each type of cancer responds to ASP2998 when given by itself or together with the standard cancer treatments. In both parts of the study, safety checks will be done at each visit, and the doctors will continue to check for medical problems throughout the study. ASP2998 will be given slowly through a tube into a vein (infusion). People will continue to receive ASP2998 until their cancer gets worse, they can't tolerate ASP2998, they start other cancer treatment, they or the doctor decides the person should stop receiving ASP2998.
Interventions
DRUGASP2998
Intravenous infusion
DRUGPembrolizumab
Intravenous infusion
DRUGEnfortumab Vedotin
Intravenous infusion
DRUGCarboplatin
Intravenous infusion
Sponsors
Astellas Pharma Global Development, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* For the ASP2998 monotherapy dose escalation (excluding urothelial and non-small cell lung cancer (NSCLC) tumor-specific backfill participants), the following criteria apply: * Participant has a confirmed diagnosis of locally advanced unresectable or metastatic solid tumors. * Participant has progressed on, is ineligible for, or has refused all available standard therapies (no limit to the number of prior treatment regimens). * Prior exposure to TROP2, stimulator of interferon genes (STING) agonist or topoisomerase I (TopI) directed therapy is allowed. * Participant must have one of the following malignancies: Urothelial carcinoma, NSCLC (nonsquamous cell histology), Gastric/ gastroesophageal junction (GEJ) cancer, Breast cancer (human epidermal growth factor receptor 2 \[HER2\]-negative; local testing for HER2 status is acceptable). * For all tumor types, any component of neuroendocrine histology is ineligible. * For the ASP2998 NSCLC second line (2L)+ Monotherapy Dose Expansion Cohort(s) (including the tumor-specific backfill participants from the monotherapy dose escalation), the following criteria apply: * Participant has locally advanced unresectable or metastatic NSCLC with known programmed cell death-1 (PD-L1) status, without actionable oncogenic alteration (AGA), according to local testing. * Participant must have histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic NSCLC that has progressed on or after receiving platinum-based chemotherapy and/or checkpoint inhibitors according to local/regional standard of care. * Participant is also eligible if there is disease progression within 12 months of receiving neoadjuvant or adjuvant therapy for resectable disease. * Participant must be eligible to receive treatment in 2L+ setting. * Participant must have had no more than 3 prior lines of therapy. * No prior exposure to TROP2, STING agonist or TopI directed therapy is allowed. * For the ASP2998 Urothelial Carcinoma Monotherapy Dose Expansion Cohort(s) (including the tumor-specific backfill participants from the monotherapy dose escalation), the following criteria apply: * Participant must have histologically or cytologically confirmed diagnosis of urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter or urethra) in locally advanced unresectable or metastatic setting that has progressed on a combination of enfortumab vedotin and pembrolizumab according to local/regional standard of care. Participant with urothelial carcinoma (transitional cell) with \< 50% squamous differentiation or mixed cell types is eligible. * Participant is also eligible if there is disease progression within 12 months of receiving adjuvant or neoadjuvant therapy for resectable disease. * Participant must be eligible to receive treatment in 2L+ setting. * Participant must have had no more than 3 prior lines of therapy. * No prior exposure to TROP2, STING agonist or TopI directed therapy is allowed. * For ASP2998 combination therapy (including the tumor-specific backfill participants from the combination therapy dose escalation), the following criteria apply for the NSCLC first line (1L) ASP2998 + Pembrolizumab + Carboplatin Dose Escalation and Expansion Cohort(s): * Participant has locally advanced unresectable or metastatic NSCLC (adenocarcinoma only, no mixed histology allowed), with known PD-L1 status, without AGA, according to local testing. * Participant is also eligible if there is disease progression \> 12 months after completing adjuvant or neoadjuvant therapy for resectable disease. * Participant has not received prior therapy for metastatic disease. * No prior exposure to TROP2, STING agonist or TopI directed therapy is allowed in dose escalation or dose expansion. * For ASP2998 combination therapy (including the tumor-specific backfill participants from the combination therapy dose escalation), the following criteria apply for the Urothelial Carcinoma 1L ASP2998 + Pembrolizumab + Enfortumab Vedotin Dose Escalation and Expansion Cohort(s): * Participant must have histologically or cytologically confirmed diagnosis of urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter or urethra) in locally advanced unresectable or metastatic setting. Participant with urothelial carcinoma (transitional cell) with \< 50% squamous differentiation or mixed cell types is eligible. * Participant is also eligible if there is disease progression \> 12 months after completing adjuvant or neoadjuvant therapy for resectable disease. * Participant has not received prior therapy for metastatic disease. * No prior exposure to TROP2, STING agonist or TopI directed therapy is allowed in dose escalation or dose expansion. * For ASP2998 combination therapy (including the tumor-specific backfill participants from the combination therapy dose escalation), the following criteria apply for the NSCLC 2L+ ASP2998 + Pembrolizumab Dose Escalation Cohort(s): * Participant has locally advanced unresectable or metastatic NSCLC with known PD-L1 status, without AGA, according to local testing. * Participant has progressed on or after receiving platinum-based chemotherapy and/or checkpoint inhibitors according to local/regional standard of care. * Participant is also eligible if there is disease progression within 12 months of receiving neoadjuvant or adjuvant therapy for resectable disease. * Participant may be eligible to receive treatment in 2L+ setting. * Participant must have had no more than 3 prior lines of therapy. * Prior exposure to TROP2, STING agonist or TopI directed therapy is allowed. * For ASP2998 combination therapy (including the tumor-specific backfill participants from the combination therapy dose escalation), the following criteria apply for the Urothelial Carcinoma 2L+ ASP2998 + Pembrolizumab Dose Escalation Cohort(s): * Participant must have histologically or cytologically confirmed diagnosis of urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter or urethra) in locally advanced unresectable or metastatic setting that has progressed on a combination of enfortumab vedotin and pembrolizumab according to local/regional standard of care. Participant with urothelial carcinoma (transitional cell) with \< 50% squamous differentiation or mixed cell types is eligible. * Participant is also eligible if there is disease progression within 12 months of receiving adjuvant or neoadjuvant therapy for resectable disease. * Participant must be eligible to receive treatment in 2L+ setting. * Participant must have had no more than 3 prior lines of therapy. * Prior exposure to TROP2, STING agonist or TopI directed therapy is allowed. * For ASP2998 combination therapy (including the tumor-specific backfill participants from the combination therapy dose escalation), the following criteria apply for the Urothelial Carcinoma 2L+ ASP2998 + Enfortumab Vedotin Dose Escalation Cohort(s): * Participant must have histologically or cytologically confirmed diagnosis of urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter or urethra) in locally advanced unresectable or metastatic setting that has progressed on a combination of enfortumab vedotin and pembrolizumab according to local/regional standard of care. Participant with urothelial carcinoma (transitional cell) with \< 50% squamous differentiation or mixed cell types is eligible. * Participant is also eligible if there is disease progression within 12 months of receiving adjuvant or neoadjuvant therapy for resectable disease. * Participant must be eligible to receive treatment in 2L+ setting. * Participant must have had no more than 3 prior lines of therapy. * Prior exposure to TROP2, STING agonist or TopI directed therapy is allowed. * Participant has a predicted life expectancy ≥ 12 weeks. * Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * 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's adverse events (AEs) (excluding alopecia) from prior anticancer therapy have improved to Grade 1 or baseline within 14 days prior to the first dose of study intervention. * Participant has adequate organ function as indicated by laboratory values (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 and at least 1 of the following conditions apply: * Not a woman of childbearing potential (WOCBP) * WOCBP who has a negative serum pregnancy test and confirmed not pregnant by medical interview at screening and agrees to follow the contraceptive guidance from the time of informed consent through 7 months after final study intervention administration. * Female participant must not be breastfeeding or lactating starting at screening and throughout the investigational period and for 7 months after final study intervention administration. * Female participant must not donate ova starting at first administration of study intervention and throughout the investigational period and for 7 months after final study intervention administration. * Male participant must agree to use contraception with female partner(s) of childbearing potential (including breastfeeding partner) throughout the treatment period and for 4 months after final study intervention administration. * Male participant must agree to remain abstinent or use a condom with pregnant partner(s) for the duration of the pregnancy throughout the investigational period and for 4 months after final study intervention administration. * Male participant must not donate sperm during the treatment period and for 4 months after final study intervention administration. * Participant agrees not to participate in another interventional study while receiving study intervention in the present study/participating in the present study (participant who is currently in the follow-up period of an interventional clinical study is allowed).
Exclusion criteria
* Participant weighs \< 40 kg during screening. * Participant has known active central nervous system (CNS) metastases. NOTE: A participant with CNS metastases that have been treated with surgery and/or radiation therapy, who is no longer taking pharmacologic doses of glucocorticoids and is neurologically stable, is eligible. Prophylactic use of anticonvulsants is permitted. * Participant has any of the following: * Any history of recurrent Grade 3 AEs/ immune-related AEs (irAEs) or history of Grade 4 irAEs related to prior anticancer therapy. * Recurrent Grade 3 or Grade 4 toxicities related to prior anticancer therapy not improved to Grade ≤ 1 or baseline per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 or higher at least 28 days prior to initiating screening. NOTE: Participant with chronic, stable Grade ≤ 2 toxicities is eligible if the toxicity has not worsened beyond Grade 2 for at least 3 months prior to C1D1 and is managed with standard of care treatment, and is considered by the investigator to be related to prior anticancer therapy. However, a participant who meets other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants with Dose Limiting Toxicities (DLTs) | Up to 21 days | A DLT is defined as any event meeting the DLT criteria occurring within 21 days of first dose on Cycle 1 Day 1 (C1D1) that cannot clearly be attributed to a cause other than ASP2998 administered in monotherapy or in combination with standard treatments. |
| Number of Participants with Treatment-Emergent Adverse Events (TEAEs) | Up to 21 Months | An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. 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 intervention. This includes events related to the comparator, if applicable, and events related to the (study) procedures. A TEAE is an AE with onset at any time from first dosing until last scheduled procedure. |
| Number of participants with laboratory value abnormalities and/or adverse events (AEs) | Up to 21 months | Number of participants with potentially clinically significant laboratory values. |
| Number of participants with vital sign abnormalities and/or AEs | Up to 19 months | Number of participants with potentially clinically significant vital sign values. |
| Number of participants with electrocardiogram (ECG) abnormalities and/or AEs | Up to 19 months | Number of participants with potentially clinically significant ECG values. |
| Number of Participants with Physical Examination (PE) abnormalities and/or AEs | Up to 19 months | Number of participants with potentially clinically significant PE values. |
| Number of Participants at each grade of Eastern Cooperative Oncology Group (ECOG) performance status score | Up to 19 months | The ECOG scale will be used to assess performance status. Scores range from 0 (fully active) to 5 (dead). Negative change scores represent an improvement. Positive scores represent a decline in performance. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) of ASP2998 per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Up to 27 months | 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 as assessed by the investigator. |
| Duration of Response (DOR) of ASP2998 per RECIST v1.1 | Up to 27 months | DOR is defined as the time from the date of first documented response (CR or PR that is subsequently confirmed) to the date of first documented progressive disease (PD) per RECIST v1.1 as assessed by the investigator or death due to any cause, whichever occurs first. |
| Disease Control Rate (DCR) of ASP2998 per RECIST v1.1 | Up to 27 months | DCR is defined as the proportion of participants whose best overall response is rated as CR, PR or stable disease (SD) per RECIST v1.1 as assessed by the investigator. |
| Progression Free Survival (PFS) per RECIST v1.1 | Up to 27 months | PFS is defined as the time from the first dose of study intervention until the date of documented PD per RECIST v1.1 as assessed by the investigator or until death for any cause, whichever comes first. |
| Overall Survival (OS) | Up to 33 months | OS is defined as the time from the first dose of study intervention until death due to any cause. |
| Pharmacokinetics (PK) of ASP2998 in plasma: area under the concentration-time curve at 21 days (AUC21d) | Up to 18 months | AUC21d will be recorded from the PK plasma samples collected. |
| PK of ASP2998 in plasma: maximum concentration (Cmax) | Up to 18 months | Cmax will be recorded from the PK plasma samples collected. |
| PK of ASP2998 in plasma: trough concentration (Ctrough) | Up to 18 months | Ctrough will be recorded from the PK plasma samples collected. |
| PK of ASP2998 in plasma: time of maximum concentration (tmax) | Up to 18 months | tmax will be recorded from the PK plasma samples collected. |
| Incidence rate of trophoblast cell surface antigen 2 (TROP2) expression in tumor | Up to 18 months | Incidence rate of TROP2 expression in tumor will be evaluated from tissue samples collected. |
| Expression levels of TROP2 in tumor | Up to 18 months | Expression levels of TROP2 expression in tumor will be evaluated from tissue samples collected. |
| Change of TROP2 expression in tumor | Up to 18 months | Change of TROP2 expression in tumor will be evaluated from tissue samples collected. |
| Change in CD8 T-cell lymphocytes in paired biopsies | Up to 18 months | Change in CD8 T-cell lymphocytes in paired biopsies will be evaluated from tissue samples collected. |
Countries
Japan, United States
Contacts
CONTACTAstellas Pharma Global Development, Inc.
STUDY_DIRECTORMedical Monitor
Astellas Pharma Global Development, Inc.
Outcome results
None listed