A Study of ASP1570 Taken by Itself or With Pembrolizumab in Adults With Solid Tumors

Study Overview
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Brief Summary
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Immune therapies work with the body's immune system to treat a number of cancers. They work with T-cells, a type of white blood cell, to target and attack specific tumors. However, some tumors can become resistant to attack by T-cells over time. They do this by sending off signals to T-cells. The researchers are finding ways to switch the T-cells back on. Early studies have shown that ASP1570 can switch T-cells back on to attack tumors. This study will provide more information on this potential new treatment in adults with advanced solid tumors. Their tumor has either grown outside of the area where it started (locally advanced and unresectable) or it has spread to other parts of the body (metastatic). Their cancer gets worse after standard therapy or they are unable to have standard therapy. People will either be treated with ASP1570 by itself, or together with another medicine called pembrolizumab. This study will be in 2 parts. In Part 1, the best dose of ASP1570 to give to people with advanced solid tumors will be worked out. Different small groups of people with advanced solid tumors will take lower to higher doses of ASP1570 by itself or with pembrolizumab. There are different doses of ASP1570, with each group staying on the same dose. There is just 1 dose of pembrolizumab. After taking the lowest dose of ASP1570, the first group will be checked for medical problems. The next group can only take the higher dose of ASP1570 if the first group on the lowest dose had no major medical problems. This will continue in the same way for each group. This means each group will take the next highest dose of ASP1570 as long as the previous group did not have any major medical problems. Each group will take tablets of ASP1570 either once or twice every day in a 21-day cycle. People taking part in Japan will stay in hospital for up to 21 days during the first treatment cycle only. People will continue with more treatment cycles on the same dose unless they have major medical problems, their cancer gets worse or the study doctor decides that person should stop treatment. People who are also receiving treatment with pembrolizumab will be infused with pembrolizumab on the first day of every other cycle of ASP1570 (once every 6 weeks). In Part 2, different small groups of people with advanced solid tumors will take the best dose of ASP1570 worked out from Part 1. The dose will not go above the highest dose that people took in Part 1 without getting major medical problems. Some groups of people will have specific advanced tumors. These include tumors from metastatic melanoma or non-small cell lung cancer (NSCLC for short). Other groups will have solid tumors that showed a response in Part 1. Again, each group will take tablets of ASP1570 once or twice every day in a 21-day cycle. Only people with NSCLC will also be infused with pembrolizumab on the first day of every other cycle of ASP1570 (once every 6 weeks). All groups will continue with more treatment cycles with ASP1570 by itself or with pembrolizumab, unless they have major medical problems, their cancer gets worse or the study doctor decides that person should stop treatment. After treatment with ASP1570, people in the study will visit their clinic 45 days after their last dose of ASP1570. People who were treated with ASP1570 and pembrolizumab will visit their clinic either 45 days after their last dose of ASP1570 or 14 days after their last dose of pembrolizumab. It will depend on which treatment was the last one they had. Then, the study clinic will contact each person in the study at least every 12 weeks until the end of the study or if they decide to leave the study.

Official Title
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A Phase 1/2 Study of ASP1570 as Monotherapy and in Combination With Pembrolizumab in Participants With Locally Advanced or Metastatic Solid Tumors

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: ASP1570
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has locally-advanced (unresectable) or metastatic solid tumor malignancy which is confirmed by available pathology records or current biopsy. 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. Monotherapy and Combination Escalation Cohorts: a) Participant has progressed on standard therapies, is no longer eligible for standard therapies or has refused standard approved therapies. Monotherapy Expansion Cohorts: Participant has progressed on standard therapies, is no longer eligible for standard therapies or has refused standard approved therapies. Participant has histologically or cytologically confirmed diagnosis of NSCLC or melanoma (for the respective RP2D Expansion Cohort to which the participant is to be enrolled into), or the tumor type in which confirmed response is observed and a Response-triggered Expansion Cohort is open (for Response-triggered Expansion Cohorts). For participants in the NSCLC monotherapy expansion cohort: participant has no actionable driver mutation (e.g., epidermal growth factor receptor [EGFR], anaplastic lymphomas kinase [ALK], neurotropic receptor tyrosine kinase [NTRK]). For participants in the NSCLC monotherapy expansion cohort: participant has progressed after receiving a checkpoint inhibitor (as monotherapy or in combination with chemotherapy) as the first-line therapy in the advanced setting. Monotherapy Dose Optimization Cohorts: a)Participant has progressed on standard therapies, is no longer eligible for standard therapies or has refused standard approved therapies and has the tumor type selected by the sponsor from the response triggered/RP2D expansion cohorts that meets the criteria for Stage 2 (for Dose Optimization). The initiation of dose optimization will depend upon the observed safety and efficacy. Combination Therapy Dose Expansion Cohorts: a) Participant has histologically or cytologically confirmed diagnosis of NSCLC and Stage IV programmed cell death protein 1(PD-L1) expression positive (tumor proportion score [TPS] ≥ 50% measured by 22C3 assay) negative for actionable molecular markers has not received prior systemic therapy for their locally advanced or metastatic NSCLC no contraindications to PD-1 or PD-L1 inhibitors. Contraindications for treatment of PD-1/PD-L1 inhibitors may include active or previously documented autoimmune disease and/or current use of immunosuppressive agents which would predict lack of benefit. Participant has an Eastern Cooperative Oncology Group Performance Status of 0 or 1. (Monotherapy cohorts and combination dose escalation cohorts only): Participant's last dose of prior antineoplastic therapy, including any immunotherapy, was at least 21 days prior to the first dose of Investigational Product (IP) administration. A participant with solid tumors that have a NTRK gene fusion without a known acquired resistance mutation or EGFR or anaplastic lymphomas kinase (ALK) mutation-positive NSCLC is allowed to remain on EGFR tyrosine kinase inhibitor (TKI), ALK inhibitor therapy or NTRK inhibitor therapy until 4 days prior to the first dose of IP. Participants who have received radiotherapy must have completed this therapy (including stereotactic radiosurgery) at least 2 weeks prior to the first dose of IP. Participant's adverse events (excluding alopecia) from prior therapy have improved to grade 1 or baseline at least 14 days prior to the first dose of IP. Note: Participants with type 1 diabetes mellitus, endocrinopathies stably maintained on appropriate replacement therapy, or skin disorders (e.g., vitiligo, psoriasis, or alopecia) not requiring systemic treatment are allowed. Participant has adequate organ function prior to start of study treatment (within 7 days prior to study drug initiation) as indicated by the following laboratory values. If a participant has received a recent blood transfusion, the laboratory tests must be obtained >= 2 weeks after any blood transfusion: Absolute Neutrophil Count (ANC) >= 1500/µL; Platelets >= 100,000/µL; Hemoglobin >= 9 g/dL (Criterion must be met without packed red blood cell transfusion within the 2 weeks prior. Participants can be on stable dose of erythropoietin (approximately ≥ 3 months); Creatinine clearance >= 60 mL/min (calculated by Cockcroft-Gault equation); Total Bilirubin either (a) <= 1.5 x ULN or (b) Direct bilirubin <= ULN and total bilirubin < 3 x ULN (for participants with Gilbert's syndrome); aspartate aminotransferase (AST) [serum glutamic oxaloacetic transaminase (SGOT)] and alanine aminotransferase (ALT) [serum glutamic pyruvic transaminase (SGPT)] <= 2.5 x ULN without liver metastases (or <= 5 x ULN if liver metastases are present); serum potassium >= 3.4 mEq/L; serum magnesium >= 1.7 mg/dL; serum ionized calcium >= 4.7 mg/dL. Thyroid stimulating hormone (TSH) within normal limits. Note: if TSH is not within normal limits at baseline, participant may still be eligible if T3 and FT4 are within the normal limits. Participant has activated partial thromboplastin time and international normalized ratio (INR) <= 1.5 x ULN and is not receiving anticoagulation. Female participant is not pregnant and at least one 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 45 days after final ASP1570 administration or at least 120 days after pembrolizumab administration, whichever occurs later. Female participant must agree not to breastfeed starting at screening and throughout the study period and for at least 45 days after final ASP1570 administration or at least 120 days after pembrolizumab administration, whichever occurs later. Female participant must not donate ova starting at first dose of IP and throughout the study period and for at least 45 days after final ASP1570 administration or at least 120 days after pembrolizumab administration, whichever occurs later. Male participant with female partner(s) of childbearing potential (including breastfeeding partner) must agree to use contraception throughout the treatment period and for at least 45 days after final ASP1570 administration or at least 120 days after pembrolizumab administration, whichever occurs later. Male participant must not donate sperm during the treatment period and for at least 45 days after final ASP1570 administration or at least 120 days after pembrolizumab administration, whichever occurs later. 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 at least 45 days after final ASP1570 administration or at least 120 days after pembrolizumab administration, whichever occurs later. Participant agrees not to participate in another interventional study while receiving study treatment in the present study. Exclusion Criteria: Participant has received investigational therapy within 21 days or 5 half-lives, whichever is shorter, prior to the first dose of ASP1570 or 4 weeks prior to the first dose of pembrolizumab. Participants may continue the following therapies until 4 days prior to the start of study intervention administration: An EGFR TKI in a participant with EGFR-activating mutations (not applicable to NSCLC monotherapy expansion cohort), ALK inhibitor in a participant with an ALK mutation (not applicable to NSCLC monotherapy expansion cohort) or, NTRK inhibitor in a participant with solid tumors that have a NTRK gene fusion without a known acquired resistance mutation (not applicable to NSCLC monotherapy expansion cohort). Participant requires or has received systemic steroid therapy or any other immunosuppressive therapy within 14 days prior to the first dose of IP. Participants using a physiologic replacement dose of hydrocortisone or its equivalent (defined as up to 30 mg per day of hydrocortisone and up to 10 mg prednisone) are allowed. Participant has received and requires strong or moderate CYP2D6 inhibitors (e.g., bupropion, fluoxetine, paroxetine, duloxetine, abiraterone) during the study. Participant has symptomatic central nervous system (CNS) metastases or participant has evidence of unstable CNS metastases even if asymptomatic (e.g., progression on scans). Participants with previously treated CNS metastases are eligible, if they are clinically stable and have no evidence of CNS progression by imaging for at least 4 weeks prior to start of study treatment and are not requiring immunosuppressive doses of systemic steroids (> 30 mg per day of hydrocortisone or > 10 mg per day of prednisone or equivalent) for no longer than 2 weeks. Participant has an active autoimmune disease. Participants with type 1 diabetes mellitus, endocrinopathies stably maintained on appropriate replacement therapy, or skin disorders (e.g., vitiligo, psoriasis, or alopecia) not requiring systemic treatment are allowed. Participant was discontinued from prior immunomodulatory therapy due to a Grade >= 3 toxicity that was mechanistically related (e.g., immune related) to the agent. Participant has a known history of human immunodeficiency virus (HIV) infection. However, participants with HIV with cluster of differentiation 4 (CD4)+ T-cell counts ≥ 350 cells/µL and no history of AIDS-defining opportunistic infections within the past 6 months are eligible. NOTE: Screening for HIV infection should be conducted per local requirements. Participant has any of the following per screening serology test: Hepatitis A virus (HAV) antibodies (immunoglobulin M [IgM]) Positive hepatitis B surface antigen (HBsAg) or detectable hepatitis B DNA. Participants with negative HBsAg, positive hepatitis B core antibody (anti-HBc) and negative hepatitis B surface antibody (anti-HBs) are eligible if hepatitis B DNA is undetectable Hepatitis C virus (HCV) antibodies unless HCV RNA is undetectable Participant has received a live or live attenuated vaccine against infectious diseases within 28 days prior to the first dose of IP. Participant has a history of pneumonitis (interstitial lung disease [ILD]), currently has pneumonitis or noninfectious pneumonitis requiring high-dose glucocorticoids. Participant has received prior radiotherapy within 2 weeks of start of study treatment or have had a history of radiation pneumonitis. Note: Participants must have recovered from all radiation-related toxicities and not require corticosteroids. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease. Participant has an infection requiring systemic therapy within 14 days prior to the first dose of IP. Participant has received a prior allogenic hematopoietic stem cell transplant or solid organ transplant. Participant is expected to require another form of antineoplastic therapy while on study treatment. Participant has had a myocardial infarction or unstable angina within 6 months prior to the start of study treatment or currently has an uncontrolled illness including, but not limited to symptomatic congestive heart failure, clinically significant cardiac disease, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Participant has inadequately controlled hypertension (defined as systolic blood pressure >150 and/or diastolic blood pressure > 100 mmHg on antihypertensive medications). Participant has a corrected QT interval using Fridericia's formula (QTcF) > 450 msec (for male and female participants) during screening. ECGs will be performed in triplicate during screening. (The average of the triplicate readings will be used in the calculation for corrected QT interval [QTc]). Participant has a prior malignancy, other than the current malignancy for which the participant is seeking treatment, active (i.e., requiring treatment or intervention) within the previous 2 years except for locally curable 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. Participant has had a major surgical procedure and has not completely recovered within 28 days prior to the first dose of IP. Participant has a history of bleeding diathesis. Participant requires use of any anticoagulation therapy. Participant has any condition which makes the participant unsuitable for study participation. Participant has a known or suspected hypersensitivity to ASP1570 or pembrolizumab (for combination therapy participants only), or any components of the formulation used. For the combination therapies, participant has received radiation therapy to the lung that is > 30 Gy within 6 months of the first dose of study treatment. For combination therapies, HIV-infected participants with a history of Kaposi sarcoma and/or Multicentric Castleman Disease.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ASP1570 Monotherapy Dose Escalation (Part 1)<br>Participants will receive daily dose of ASP1570 in a 21-day cycle. | Drug: ASP1570<br>* Oral tablet<br>|
| Experimental: ASP1570 Monotherapy Tumor Specific Dose Expansion - Response-triggered Tumor (Part 2)<br>Participants will receive ASP1570 in a 21-day cycle in tumor-specific cohort if dose escalation cohort had partial response (PR) or complete response (CR) in same tumor type at a dose that has been cleared and deemed tolerable. | Drug: ASP1570<br>* Oral tablet<br>|
| Experimental: ASP1570 Monotherapy Dose Expansion - Melanoma (Part 2)<br>Participants who have melanoma will receive recommended Phase 2 dose (RP2D) of ASP1570 in a 21-day cycle. | Drug: ASP1570<br>* Oral tablet<br>|
| Experimental: ASP1570 Monotherapy Dose Expansion - Non-Small Cell Lung Carcinoma (NSCLC) (Part 2)<br>Participants who have NSCLC will receive RP2D of ASP1570 daily in a 21-day cycle. | Drug: ASP1570<br>* Oral tablet<br>|
| Experimental: ASP1570 + Pembrolizumab Combination therapy Dose Escalation (Part 1)<br>Participants will receive daily dose of ASP1570 in a 21-day cycle. Pembrolizumab will be administered every 6 weeks on day 1 of every other ASP1570 cycle. | Drug: ASP1570<br>* Oral tablet<br>Drug: Pembrolizumab<br>* Intravenous Infusion<br>|
| Experimental: ASP1570 + Pembrolizumab Combination therapy Dose Expansion - NSCLC (Part 2)<br>Participants who have NSCLC will receive RP2D of ASP1570 daily in a 21-day cycle. Pembrolizumab will be administered every 6 weeks on day 1 of every other ASP1570 cycle. | Drug: ASP1570<br>* Oral tablet<br>Drug: Pembrolizumab<br>* Intravenous Infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose Limiting Toxicities (DLTs) for ASP1570 Single Agent | 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. | 21 days | 
| Number of Participants with Adverse Events (AEs) | Adverse events (AEs) will be coded using medical dictionary for regulatory activities (MedDRA). An AE is any untoward medical occurrence in a participant temporally associated with the use of study IP, whether or not considered related to the study IP. 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. | Up to 27 months | 
| Change from baseline to 45 days after End of Treatment (EOT) in laboratory values | National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) grade changes from baseline to highest post-baseline grade will be assessed. | Baseline and 45 days after EOT | 
| Number of participants with vital sign abnormalities and/or AEs | Number of participants with potentially clinically significant vital sign values. | Up to 27 months | 
| Number of participants with electrocardiogram (ECG) abnormalities and/or AEs | Number of participants with potentially clinically significant ECG values. | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) of ASP1570 per Immune Response Evaluation Criteria in Solid Tumors (iRECIST) | ORR is defined as the proportion of participants for each dose level whose best overall response is rated as Complete Response (CR) or Partial Response (PR) per iRECIST. | Up to 27 months | 
| ORR of ASP1570 per Response Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1) | ORR is defined as the proportion of participants for each dose level whose best overall response is rated as Complete Response (CR) or Partial Response (PR) per RECIST 1.1. | Up to 27 months | 
| Duration of Response (DOR) of ASP1570 per iRECIST | DOR will be calculated only for the subgroup of participants with confirmed response CR/PR per iRECIST. | Up to 27 months | 
| Duration of Response (DOR) of ASP1570 per RECIST 1.1 | DOR will be calculated only for the subgroup of participants with confirmed response CR/PR per RECIST 1.1. | Up to 27 months | 
| Disease Control Rate (DCR) of ASP1570 per iRECIST | DCR is defined as the proportion of participants for each dose level whose best overall response is rated as confirmed CR, PR or SD per iRECIST. | Up to 27 months | 
| Disease Control Rate (DCR) of ASP1570 per RECIST 1.1 | DCR is defined as the proportion of participants for each dose level whose best overall response is rated as confirmed CR, PR or SD per RECIST 1.1. | Up to 27 months | 
| Pharmacokinetics of ASP1570 in plasma: Maximum Concentration (Cmax) | Cmax will be recorded from the PK plasma samples collected. | Up to 27 months | 
| Pharmacokinetics of ASP1570 in plasma: Time of Maximum Concentration (tmax) | tmax will be recorded from the PK plasma samples collected. | Up to 27 months | 
| Pharmacokinetics of ASP1570 in plasma: Area under the plasma concentration-time curve during a dosage interval (AUCtau) | AUCtau will be recorded from the PK plasma samples collected. | Up to 27 months | 
| Pharmacokinetics of ASP1570 in plasma: Trough plasma concentration (Ctrough) | Ctrough will be recorded from the PK plasma samples collected. | Up to 27 months | 
| Changes in tumor infiltration with CD4/CD8 cells | Proportion of participants with changes in infiltration of CD4/CD8 cells. | Up to 27 months | 
| Level of proliferation of CD4/CD8/Ki67+ cells | Proportion of participants with changes in level of proliferation of CD4/CD8/Ki67+ cells in the tumor microenvironment resulting from ASP1570. | Up to 27 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced Solid Tumors, ASP1570, Pembrolizumab