A Phase 1b/2 Study of ASP2998 as Monotherapy and in Combination With Standard Therapies in Participants With Locally Advanced Unresectable or Metastatic Solid Tumors
Overview
- Phase
- Phase 1
- Status
- Recruiting
- Enrollment
- 428
- Locations
- 7
- Primary Endpoint
- Number of participants with electrocardiogram (ECG) abnormalities and/or AEs
Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts 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, 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.
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 exclusion criteria will be excluded from the study regardless of the above provisions.
- •Participant has active or prior autoimmune or inflammatory disorders requiring systemic anti-inflammatory or immunosuppressive therapy within the past 3 years. Participants with type 1 diabetes mellitus or endocrinopathies stably maintained on appropriate replacement therapy will not be excluded.
- •Participant has uncontrolled diabetes mellitus. For cohorts receiving enfortumab vedotin, uncontrolled diabetes is defined as hemoglobin A1c (HbA1c) of ≥ 8% or HbA1c of 7% to \< 8% with associated diabetes symptoms (polyuria or polydipsia).
- •Participant has leptomeningeal disease as a manifestation of the current malignancy.
- •Participant has a known additional malignancy that requires active treatment, with the exception of any of the following:
- •Locally curable malignancies that have been apparently cured with no recurrence in the past 2 years.
Arms & Interventions
ASP2998 Combination Therapy Dose Expansion (Tumor Specific)
Participants with select tumor types will receive ASP2998 in a 21-day cycle at dose level(s) based on emerging data.
Intervention: Carboplatin (Drug)
ASP2998 Dose Escalation
Participants with urothelial carcinoma (UC), NSCLC, gastric/GEJ cancer or breast cancer (HER2-negative) will receive sequential doses of ASP2998 in a 21-day cycle.
Intervention: ASP2998 (Drug)
ASP2998 Dose Expansion
Participants with UC or NSCLC will receive ASP2998 in a 21-day cycle with dose level(s) selected from dose escalation.
Intervention: ASP2998 (Drug)
ASP2998 Monotherapy Dose Escalation (Tumor Specific)
Participants with select tumor types will receive ASP2998 in a 21-day cycle at dose level(s) based on emerging data.
Intervention: ASP2998 (Drug)
ASP2998 Monotherapy Dose Expansion (Tumor Specific)
Participants with select tumor types will receive ASP2998 in a 21-day cycle at dose level(s) based on emerging data.
Intervention: ASP2998 (Drug)
ASP2998 Combination Therapy Dose Escalation (Tumor Specific)
Participants with select tumor types will receive ASP2998 in a 21-day cycle at dose level(s) based on emerging data.
Intervention: ASP2998 (Drug)
ASP2998 Combination Therapy Dose Escalation (Tumor Specific)
Participants with select tumor types will receive ASP2998 in a 21-day cycle at dose level(s) based on emerging data.
Intervention: Pembrolizumab (Drug)
ASP2998 Combination Therapy Dose Escalation (Tumor Specific)
Participants with select tumor types will receive ASP2998 in a 21-day cycle at dose level(s) based on emerging data.
Intervention: Enfortumab Vedotin (Drug)
ASP2998 Combination Therapy Dose Escalation (Tumor Specific)
Participants with select tumor types will receive ASP2998 in a 21-day cycle at dose level(s) based on emerging data.
Intervention: Carboplatin (Drug)
ASP2998 Combination Therapy Dose Expansion (Tumor Specific)
Participants with select tumor types will receive ASP2998 in a 21-day cycle at dose level(s) based on emerging data.
Intervention: Pembrolizumab (Drug)
ASP2998 Combination Therapy Dose Expansion (Tumor Specific)
Participants with select tumor types will receive ASP2998 in a 21-day cycle at dose level(s) based on emerging data.
Intervention: ASP2998 (Drug)
ASP2998 Combination Therapy Dose Expansion (Tumor Specific)
Participants with select tumor types will receive ASP2998 in a 21-day cycle at dose level(s) based on emerging data.
Intervention: Enfortumab Vedotin (Drug)
Outcomes
Primary Outcomes
Number of participants with electrocardiogram (ECG) abnormalities and/or AEs
Time Frame: Up to 19 months
Number of participants with potentially clinically significant ECG values.
Number of Participants at each grade of Eastern Cooperative Oncology Group (ECOG) performance status score
Time Frame: 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.
Number of participants with vital sign abnormalities and/or AEs
Time Frame: Up to 19 months
Number of participants with potentially clinically significant vital sign values.
Number of Participants with Dose Limiting Toxicities (DLTs)
Time Frame: 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)
Time Frame: 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)
Time Frame: Up to 21 months
Number of participants with potentially clinically significant laboratory values.
Number of Participants with Physical Examination (PE) abnormalities and/or AEs
Time Frame: Up to 19 months
Number of participants with potentially clinically significant PE values.
Secondary Outcomes
- PK of ASP2998 in plasma: time of maximum concentration (tmax)(Up to 18 months)
- Disease Control Rate (DCR) of ASP2998 per RECIST v1.1(Up to 27 months)
- Progression Free Survival (PFS) per RECIST v1.1(Up to 27 months)
- PK of ASP2998 in plasma: trough concentration (Ctrough)(Up to 18 months)
- Expression levels of TROP2 in tumor(Up to 18 months)
- Change in CD8 T-cell lymphocytes in paired biopsies(Up to 18 months)
- Objective Response Rate (ORR) of ASP2998 per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1(Up to 27 months)
- Incidence rate of trophoblast cell surface antigen 2 (TROP2) expression in tumor(Up to 18 months)
- Change of TROP2 expression in tumor(Up to 18 months)
- Duration of Response (DOR) of ASP2998 per RECIST v1.1(Up to 27 months)
- Overall Survival (OS)(Up to 33 months)
- Pharmacokinetics (PK) of ASP2998 in plasma: area under the concentration-time curve at 21 days (AUC21d)(Up to 18 months)
- PK of ASP2998 in plasma: maximum concentration (Cmax)(Up to 18 months)