Clinical trial NCT05083481: A Study of ASP1570 Alone or in Combination With Pembrolizumab or Standard Therapies in Adults With Solid Tumors
Official title: A Phase 1/2 Study of ASP1570 as Monotherapy and in Combination With Pembrolizumab or Standard Therapies Including Chemotherapy and/or Immunotherapy in Participants With Locally Advanced or Metastatic Solid Tumors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Advanced Solid Tumors
Keywords: Advanced Solid Tumors
ASP1570
Pembrolizumab
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2021-10-19
Enrollment: 310
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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.

Before a treatment can be approved for use, clinical studies need to be done. This study will provide more information on ASP1570 in adults with advanced solid tumors. ASP1570 will either be given by itself, or given with another medicine called pembrolizumab, or given with a standard cancer therapy.

The main aims of this study are：

* To check the safety of ASP1570
* To check how well ASP1570 is tolerated
* To find a suitable dose of ASP1570

This study is for 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. The study doctors can give more advice about who can take part.

This study will be in 2 parts.

In Part 1, the most suitable 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. People will either be given ASP1570 by itself, ASP1570 with another medicine called pembrolizumab, or ASP1570 with a standard cancer therapy. The study treatment given depends on the type of cancer people have. There are different doses of ASP1570, with each group staying on the same dose. There is just 1 dose of pembrolizumab. The dose of a standard cancer therapy depends on its label. 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 tolerates the lowest dose . This will continue in the same way for each group.

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 can't tolerate the study treatment, their cancer gets worse or the study doctor decides that person should stop treatment. People who also receive treatment with pembrolizumab will be infused with pembrolizumab on the first day of every other cycle of ASP1570 (once every 6 weeks). People who are receiving standard cancer therapy (with ASP1570) will be treated according to its label.

In Part 2, different small groups of people with advanced solid tumors will take the most suitable dose of ASP1570 worked out from Part 1. The dose will not go above the highest dose that people could tolerate from Part 1. Some groups of people will have specific advanced tumors. These include colorectal cancer or non-small cell lung cancer (NSCLC for short). Again, each group will take tablets of ASP1570 once or twice every day in a 21-day or 28-day cycle. People with NSCLC will also receive docetaxel, one of the standard cancer therapies. People with stable colorectal cancer (known as CRC with microsatellite stability, or MSS-CRC) will also receive another standard cancer therapy called TAS-102 with bevacizumab. The standard cancer therapies will be given according to their label. People with solid tumors will also receive 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 with pembrolizumab, or with one of the standard cancer therapies unless they can't tolerate the study treatment, their cancer gets worse or the study doctor decides that person should stop treatment.


Eligibility criteria: 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 and China-specific Safety Lead-in Cohort:

  a) Participant has progressed on standard therapies, is no longer eligible for standard therapies or has refused standard approved therapies (no limit to the number of prior treatment regimens). (UNIQUE to China: Tumor types will be determined at the sponsor's discretion.)
* Monotherapy Expansion Cohorts and China-specific Safety Lead-in Cohort:

  a) Participant has histologically confirmed diagnosis of locally advanced or metastatic MSS-CRC and has progressed was intolerant to at least 2 prior cancer therapy regimens administered for metastatic disease.
* Monotherapy Dose Optimization Cohorts:

  a) Participant has histologically confirmed diagnosis of locally advanced or metastatic MSS-CRC and has progressed or was intolerant to at least 2 prior cancer therapy regimens administered for metastatic disease.
* Combination Therapy Cohorts:

  a) For NSCLC Combination Therapy Cohort only:
* Participant has histologically confirmed or cytologically confirmed diagnosis of Stage IV NSCLC and has progressed on or after platinum-based chemotherapy and/or checkpoint inhibitors.
* Participant is eligible to receive docetaxel. b) For MSS CRC Combination Therapy Cohort only:
* Participant has histologically confirmed diagnosis of locally advanced or metastatic MSS-CRC.
* Participant must have progressed or was intolerant to at least 2 prior cancer therapy regimens administered for metastatic disease.
* Participant is eligible to receive TAS-102 and bevacizumab.

Monotherapy and Combination Therapy Additional Backfill Participants:

* Participant has histologically confirmed diagnosis of Stage IV NSCLC and has progressed on or after receiving platinum based chemotherapy and/or checkpoint inhibitors in the first line of therapy.
* Participant has an Eastern Cooperative Oncology Group (ECOG) 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 study intervention 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 study intervention. Note: This is not applicable to participants with NSCLC in the combination dose expansion cohort.
* Participants who have received radiotherapy must have completed this therapy (including stereotactic radiosurgery) at least 2 weeks prior to the first dose of study intervention.
* Participant's adverse events (excluding alopecia) from prior therapy have resolved or improved to grade 1 at least 14 days prior to the first dose of study intervention. 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 intervention treatment 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); 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/or 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 administration of pembrolizumab or standard therapies, 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 administration of pembrolizumab or standard therapies, whichever occurs later.
* Female participant must not donate ova starting at first dose of study intervention and throughout the study period and for at least 45 days after final ASP1570 administration or at least 120 days after administration of pembrolizumab or standard therapies, 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 administration of pembrolizumab or standard therapies, 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 administration of pembrolizumab or standard therapies, 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 administration of pembrolizumab or standard therapies, 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, (UNIQUE to China: and/or antitumor Chinese traditional medicine within 28 days) prior to the first dose of ASP1570 or 4 weeks prior to the first dose of pembrolizumab or standard therapies.
* Participants may continue the following therapies until 4 days prior to the start of study intervention administration:

  1. An EGFR TKI in a participant with EGFR-activating mutations (not applicable to NSCLC participants),
  2. ALK inhibitor in a participant with an ALK mutation (not applicable to NSCLC participants) or,
  3. NTRK inhibitor in a participant with solid tumors that have a NTRK gene fusion without a known acquired resistance mutation (not applicable to NSCLC participants).
* 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 10 mg prednisone) are allowed.
* Participant 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 (\> 10 mg per day of prednisone or equivalent) for no longer than 2 weeks.
* Participant has an 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 study intervention.
* Participant has a history of immune related pneumonitis (interstitial lung disease \[ILD\]), currently has 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 study intervention.
* 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 study intervention.
* Participant has a history of bleeding diathesis that makes the participant unsuitable for study participation.
* Participant requires use of any anticoagulation therapy that makes the participant unsuitable for study participation.
* Participant has any condition that makes the participant unsuitable for study participation.
* Participant has a known or suspected hypersensitivity to ASP1570. For participants entering combination therapy, they have a known or suspected hypersensitivity to the respective standard therapy study intervention (pembrolizumab, docetaxel, TAS 102 and/or bevacizumab), 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 intervention.
* All Solid Tumors Combination Therapy Cohort only: HIV-infected participants with a history of Kaposi sarcoma and/or multicentric Castleman disease.
* Dose expansion combination therapy, China safety lead in and backfill participants: NSCLC participants with known actionable driver mutation (e.g., EGFR, ALK, NTRK.

Primary outcomes:
measure: Incidence of Dose Limiting Toxicities (DLTs) for ASP1570 Single Agent
timeFrame: 21 days
measure: Number of Participants with Adverse Events (AEs)
timeFrame: Up to 27 months
measure: Change from baseline to 45 days after End of Treatment (EOT) in laboratory values
timeFrame: Baseline and 45 days after EOT
measure: Number of participants with vital sign abnormalities and/or AEs
timeFrame: Up to 27 months
measure: Number of participants with electrocardiogram (ECG) abnormalities and/or AEs
timeFrame: Up to 24 months
Secondary outcomes:
measure: Objective Response Rate (ORR) of ASP1570 per Immune Response Evaluation Criteria in Solid Tumors (iRECIST)
timeFrame: Up to 27 months
measure: ORR of ASP1570 per Response Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1)
timeFrame: Up to 27 months
measure: Duration of Response (DOR) of ASP1570 per iRECIST
timeFrame: Up to 27 months
measure: Duration of Response (DOR) of ASP1570 per RECIST 1.1
timeFrame: Up to 27 months
measure: Disease Control Rate (DCR) of ASP1570 per iRECIST
timeFrame: Up to 27 months
measure: Disease Control Rate (DCR) of ASP1570 per RECIST 1.1
timeFrame: Up to 27 months
measure: Pharmacokinetics of ASP1570 in plasma: Maximum Concentration (Cmax)
timeFrame: Up to 27 months
measure: Pharmacokinetics of ASP1570 in plasma: Time of Maximum Concentration (tmax)
timeFrame: Up to 27 months
measure: Pharmacokinetics of ASP1570 in plasma: Area under the plasma concentration-time curve during a dosage interval (AUCtau)
timeFrame: Up to 27 months
measure: Pharmacokinetics of ASP1570 in plasma: Trough plasma concentration (Ctrough)
timeFrame: Up to 27 months
measure: Changes in tumor infiltration with CD4/CD8 cells
timeFrame: Up to 27 months
measure: Level of proliferation of CD4/CD8/Ki67+ cells
timeFrame: Up to 27 months
Other outcomes:
Locations:
city: Fullerton
country: United States
facility: Providence Medical Foundation
state: California
city: Los Angeles
country: United States
facility: California Research Institute
state: California
city: Los Angeles
country: United States
facility: USC/Norris Comprehensive Cancer Center
state: California
city: Sarasota
country: United States
facility: Florida Cancer Specialist & Research Institute Sarasota
state: Florida
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Lexington
country: United States
facility: University of Kentucky Medical Center MCC-CRO
state: Kentucky
city: Bethesda
country: United States
facility: American Oncology Partners
state: Maryland
city: Omaha
country: United States
facility: Nebraska Methodist Hospital
state: Nebraska
city: Morristown
country: United States
facility: Atlantic Health System/Morristown Medical Center
state: New Jersey
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: SCRI Oncology Partners
state: Tennessee
city: Dallas
country: United States
facility: Mary Crowley Research Center
state: Texas
city: Madison
country: United States
facility: University of Wisconsin Clinical Science Center
state: Wisconsin
city: Beijing
country: China
facility: Beijing Cancer Hospital
city: Shanghai
country: China
facility: Shanghai East Hospital
city: Besancon Cedex
country: France
facility: FR33007
city: Bordeaux
country: France
facility: Site FR33002
city: Paris
country: France
facility: FR33008
city: Poitiers
country: France
facility: FR33001
city: St Herblain
country: France
facility: FR33005
city: Toulouse
country: France
facility: FR33009
city: Yokohama
country: Japan
facility: Kanagawa Cancer Center
state: Kanagawa
city: Sunto-gun
country: Japan
facility: Shizuoka Cancer Center
state: Shizuoka
city: Chuo-ku
country: Japan
facility: National Cancer Center Hospital
state: Tokyo
city: Koto-ku
country: Japan
facility: Cancer Institute Hospital Of JFCR
state: Tokyo
city: Seoul
country: Korea, Republic of
facility: KR82002
city: Río Piedras
country: Puerto Rico
facility: Site PR1601
city: A Coruña, Barcelona
country: Spain
facility: Site ES34005
city: Avda
country: Spain
facility: Site ES34004
city: Madrid
country: Spain
facility: Site ES34002
city: Malaga
country: Spain
facility: Site ES34007
city: Málaga
country: Spain
facility: ES34008
city: Pozuelo de Alarcón
country: Spain
facility: Site ES34006
city: Santiago De Compostela
country: Spain
facility: ES34003
Study officials:
affiliation: Astellas Pharma Global Development, Inc.
name: Medical Director
role: STUDY_DIRECTOR
References: