A Study of ASP1570 Alone or in Combination with Pembrolizumab or Standard Therapies in Adults with Solid Tumors

Phase 1/2

Recruiting

Conditions: Advanced Solid Tumors

Interventions: Drug: ASP1570
Drug: Trifluridine + Tipiracil
Drug: pembrolizumab
Drug: Docetaxel
Drug: Bevacizumab

Registration Number: 2023-505084-37-00

Lead Sponsor: Astellas Pharma Global Development Inc.

Brief Summary: To determine the safety and tolerability of ASP1570 as monotherapy and in combination with pembrolizumab or standard therapies

To determine the RP2D and/or MTD, optimized dose of ASP1570 as monotherapy and in combination with pembrolizumab or standard therapies

Detailed Description: Not available

Recruitment & Eligibility

Status: Ongoing, recruiting

Sex: Not specified

Target Recruitment: 98

Inclusion Criteria

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent and privacy language (not applicable to China sites) as per national regulations (e.g., Health Insurance Portability and Accountability Act authorization for US study sites) must be obtained from the participant prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
Participant has adequate organ function prior to start of study intervention 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); 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/or FT4 are within the normal limits.
Participant has activated partial thromboplastin time and international normalized ratio (INR) ≤ 1.5 × ULN and is not receiving anticoagulation.
Female participant is not pregnant and at least one of the following conditions apply: a. Not a woman of childbearing potential (WOCBP) b. 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 IP 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.
Participant is considered an adult according to local regulation at the time of signing the ICF.
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.
For Monotherapy and Combination Escalation Cohorts: Participant has progressed or no longer eligible for standard therapies or has refused standard approved therapies or Participant has Stage IV NSCLC and has progressed on or after platinum-based chemotherapy and/or checkpoint inhibitors and are eligible to receive docetaxel or Participant has confirmed diagnosis of locally advanced or metastatic MSS-CRC, progressed on 2 prior cancer therapy regimens and are eligible to receive TAS-102 and bevacizumab
Participant has an Eastern Cooperative Oncology Group Performance (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 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 AEs (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.

Exclusion Criteria

Participant has received investigational therapy within 21 days or 5 half-lives, whichever is shorter, (UNIQUE to China: and/or anti-tumor 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: a. An EGFR TKI in a participant with EGFR-activating mutations (not applicable to NSCLC participants), b. ALK inhibitor in a participant with an ALK mutation (not applicable to NSCLC participants) or, c. 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 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 immune related pneumonitis (interstitial lung disease), currently has pneumonitis requiring high-dose glucocorticoids.
Participant has a history of bleeding diathesis that, in the investigator’s opinion, makes the participant unsuitable for study participation.
Participant requires use of any anticoagulation therapy that, in the investigator’s opinion, makes the participant unsuitable for study participation
Participant has any condition, that, in the investigator’s opinion, 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 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 Cohorts only, HIV-infected participants with a history of Kaposi sarcoma and/or multicentric Castleman disease.
Participant has an infection requiring systemic therapy within 14 days prior to the first dose of study intervention.
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 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 received a prior allogeneic 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]).
(Dose expansion combination therapy, China safety lead-in and backfill participants): NSCLC participants with known actionable driver mutation (e.g., EGFR, ALK, neurotropic receptor tyrosine kinase [NTRK]).
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 in the judgment of the investigator.
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: a. Hepatitis A virus antibodies (immunoglobulin M [IgM]) b. 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 c. 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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
ASP1570 + TAS-102 + Bevacizumab Combination therapy Dose Expansion - MSS-CRC 3L+ (Part 2)	Trifluridine + Tipiracil	Participants who have MSS-CRC will receive ASP1570 daily in a 28-day cycle. TAS-102 (Trifluridine + Tipiracil) will be administered on days 1 through 5 and days 8 through 12 of each 28-day cycle. Bevacizumab will be administered every 2 weeks.
ASP1570 Monotherapy Dose Expansion - Food Effect (Part 2)	ASP1570	Participants will receive RP2D of ASP1570 after the meal in a 21-day cycle. This cohort will be opened at the discretion of the sponsor.
ASP1570 Monotherapy Dose Expansion - Prophylactic (Part 2)	ASP1570	Participants will receive RP2D of ASP1570 along with the standard prophylactic medication in a 21-day cycle. This cohort will be opened at the discretion of the sponsor.
ASP1570 Monotherapy Dose Expansion - Intermittent dosing (Part 2)	ASP1570	Participants will receive RP2D of ASP1570 with some periodical drug holiday in a 21-day cycle. This cohort will be opened at the discretion of the sponsor.
ASP1570 Monotherapy Dose Expansion - Stepwise dosing (Part 2)	ASP1570	Participants will receive ASP1570 administered by intra-subject dose escalation with gradual multiple dose steps (e.g., 3 steps) and increased dose up to RP2D in a 21-day cycle. This cohort will be opened at the discretion of the sponsor.
ASP1570 Monotherapy Dose Expansion Microsatellite stable - colorectal cancer (MSS-CRC) (Part 2)	ASP1570	Participants who have MSS-CRC will receive ASP1570 in a 21-day cycle.
ASP1570 + pembrolizumab Combination therapy Dose Escalation (Part 1)	ASP1570	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.
ASP1570 Monotherapy Dose Escalation (Part 1)	ASP1570	Participants will receive daily dose of ASP1570 in a 21-day cycle.
ASP1570 + pembrolizumab Combination therapy Dose Escalation (Part 1)	pembrolizumab	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.
ASP1570 + Docetaxel Combination therapy Dose Expansion - NSCLC 2L+ (Part 2)	ASP1570	Participants who have NSCLC will receive RP2D of ASP1570 daily in a 21-day cycle. Docetaxel will be administered every 6 weeks on day 1 of every other ASP1570 cycle.
ASP1570 + Docetaxel Combination therapy Dose Expansion - NSCLC 2L+ (Part 2)	Docetaxel	Participants who have NSCLC will receive RP2D of ASP1570 daily in a 21-day cycle. Docetaxel will be administered every 6 weeks on day 1 of every other ASP1570 cycle.
ASP1570 + TAS-102 + Bevacizumab Combination therapy Dose Expansion - MSS-CRC 3L+ (Part 2)	ASP1570	Participants who have MSS-CRC will receive ASP1570 daily in a 28-day cycle. TAS-102 (Trifluridine + Tipiracil) will be administered on days 1 through 5 and days 8 through 12 of each 28-day cycle. Bevacizumab will be administered every 2 weeks.
ASP1570 + TAS-102 + Bevacizumab Combination therapy Dose Expansion - MSS-CRC 3L+ (Part 2)	Bevacizumab	Participants who have MSS-CRC will receive ASP1570 daily in a 28-day cycle. TAS-102 (Trifluridine + Tipiracil) will be administered on days 1 through 5 and days 8 through 12 of each 28-day cycle. Bevacizumab will be administered every 2 weeks.

Primary Outcome Measures

Name	Time	Method
Safety variables (e.g., incidence of DLTs and AEs; change from baseline in laboratory tests, vital signs and ECG)		Safety variables (e.g., incidence of DLTs and AEs; change from baseline in laboratory tests, vital signs and ECG)

Secondary Outcome Measures

Name	Time	Method
ORR, DOR, and DCR of ASP1570 as monotherapy and in combination with pembrolizumab or standard therapies per iRECIST and RECIST 1.1		ORR, DOR, and DCR of ASP1570 as monotherapy and in combination with pembrolizumab or standard therapies per iRECIST and RECIST 1.1
Selected pharmacokinetic parameters of ASP1570 as monotherapy and in combination with pembrolizumab or standard therapies in plasma: Cmax, tmax, AUCtau and Ctrough		Selected pharmacokinetic parameters of ASP1570 as monotherapy and in combination with pembrolizumab or standard therapies in plasma: Cmax, tmax, AUCtau and Ctrough
Changes in tumor infiltration with CD4/CD8 cells and level of their proliferation (CD4/CD8, Ki67+)		Changes in tumor infiltration with CD4/CD8 cells and level of their proliferation (CD4/CD8, Ki67+)

Trial Locations

Locations (14): Institut Catala D'oncologia
🇪🇸
L'hospitalet De Llobregat, Spain
Hospital General Universitario Gregorio Maranon
🇪🇸
Madrid, Spain
Complexo Hospitalario Universitario De Santiago
🇪🇸
Santiago De Compostela, Spain
Hospital Universitario Y Politecnico La Fe
🇪🇸
Valencia, Spain
Hospital Universitario Virgen De La Victoria
🇪🇸
Malaga, Spain
Hospital Universitario Quironsalud Madrid
🇪🇸
Pozuelo De Alarcon, Spain
Hospital Universitario Regional De Malaga
🇪🇸
Malaga, Spain
Institut Gustave Roussy
🇫🇷
Villejuif, France
Institut Bergonie
🇫🇷
Bordeaux, France
Institut De Cancerologie De L Ouest
🇫🇷
St Herblain, France
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Institut Catala D'oncologia
🇪🇸L'hospitalet De Llobregat, Spain
Juan Jesus Martin Liberal
Site contact
+34932607744
jmartinliberal@iconcologia.net