PRE-I-SPY Phase I/Ib Oncology Platform Program

Study Overview
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Brief Summary
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I-SPY Phase I/Ib (I-SPY-P1) is an open-label, multisite platform study designed to evaluate single agents or combinations in a metastatic treatment setting that may be relevant for breast cancer patients with the overall goal of moving promising drug regimens into the I-SPY 2 SMART Design Trial (NCT01042379) and/or other oncology-based trials in a timely manner.

Detailed Description
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The PRE-I-SPY/I-SPY-P1 study is a platform trial with multiple ongoing drug regimen arms. In most cases, the treatment arm will have a dose-finding group (Part 1) and a dose-expansion group (Part 2). Eligibility criteria will vary according to the experimental regimen. Participant eligibility may vary according to the arm or the part within the study arm, including with respect to diagnosis. Arms could include participants diagnosed with certain solid tumors or specifically with breast cancer. Arms may restrict enrollment to a certain molecular pathway abnormality or histologic diagnosis. The trial allows for various study arm designs, with the goal to complete analysis of a study arm in 12 to 18 months.

Official Title
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PRE-Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging And moLecular Analysis: A Phase I/Ib Platform Trial

Conditions
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HER2-positive Breast Cancer, Metastatic Cancer, Metastatic Breast Cancer, Metastatic, HER2-positive Metastatic Breast Cancer, HER2 Mutation-Related Tumors, HER-2 Protein Overexpression, HER2-negative Breast Cancer, Triple Negative Breast Cancer, HR Positive, Hormone Receptor-positive Breast Cancer, Estrogen Receptor Positive Tumor, Progesterone Receptor-positive Breast Cancer, Hormone Receptor Negative Breast Carcinoma, Solid Tumor, Solid Tumor, Adult, Solid Carcinoma, HER2 Low Breast Cancer, HER2 Low Breast Carcinoma, ER Positive Breast Cancer, PR-positive Breast Cancer

Intervention / Treatment
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* Drug: ALX148
* Drug: Fam-Trastuzumab Deruxtecan-Nxki
* Drug: Zanidatamab
* Drug: Tucatinib


Participation Criteria
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Eligibility Criteria
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General Inclusion Criteria (GIC): GIC1: The participant must have ability to understand and willingness to provide signed written informed consent prior to any study related assessments and procedures and for collection of archival FFPE blocks (freshly cut 14 unstained tumor slides would be acceptable). GIC2: Age ≥ 18 years at the time of signing the informed consent GIC3: Gender: Male or female (premenopausal and postmenopausal) GIC4: ECOG performance status Grade 0-2 GIC5: Estimated life expectancy > 12 weeks at the start of investigational medicinal product (IMP) treatment. GIC6: Adequate organ function, evidenced by the following laboratory results within 30 days of the start of IMP: Absolute neutrophil count ≥ 1,500/mm3 Platelet count ≥ 100,000/mm3 Hemoglobin ≥ 9.0 g/dL with no blood transfusion in the past 28 days Total bilirubin ≤ 1.5 x the upper limit of normal (ULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN Estimated Creatinine clearance (using Cockcroft-Gault formula) ≥ 60 mL/min for small molecules and >30 mL/min for monoclonal antibodies unless otherwise specified in the Arm Specific Eligibility. These cut-off values may be modified with supporting data for specific drug regimens. GIC7: Non-Pregnant: Serum or urine pregnancy test must be negative within 14 days of IMP treatment start in women of childbearing potential. Pregnancy testing does not need to be pursued in patients who are judged as postmenopausal before enrollment, or who have undergone bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation. If male, they must agree to refrain from donating sperm during treatment. GIC8: Contraception: Women of childbearing potential and men must be willing to use adequate contraception for the duration of protocol treatment. Additional information regarding contraception for the specific treatment arm will be added to the drug arm description. Adequate contraception is defined as one highly effective form (i.e., abstinence, (fe)male sterilization) OR two effective forms (e.g., non-hormonal IUD and condom / occlusive cap with spermicidal foam / gel / film / cream / suppository). GIC9: Prior therapy effects: Resolution of all acute toxic effects of prior therapy, including radiotherapy, to grade ≤1 and neuropathy to grade ≤2 (except toxicities not considered a safety risk for the patient) and recovery from surgical procedures. GIC10: Participant compliance: Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Additional arm specific inclusion criteria as needed by drug arm regimen General Exclusion Criteria (GEC): GEC1: Wash out periods: No other anticancer therapy within the following periods: chemotherapy or investigational agents, 3 weeks mitomycin C and nitrosoureas, 6 weeks radiotherapy, 3 weeks targeted therapy, 2 weeks MAbs, ADCs, and immunotherapy, 3 weeks endocrine therapy, no washout needed GEC2: Concurrent therapy with other Investigational Products. GEC3: Prior history of drug/regimen hypersensitivity: History of infusion-related reactions and/or hypersensitivity to IMP or excipients of the study drug/drugs which led to permanent discontinuation of the treatment. GEC4: Uncontrolled intercurrent illness including (active infection, diabetes, pulmonary embolism in the past 6 months, or psychiatric illness/social situations that would limit compliance with study requirements). GEC5: Cardiovascular disease: History (within 6 months prior to start IMP) of clinically significant cardiovascular disease such as unstable angina, congestive heart failure (CHF), myocardial infarction, uncontrolled hypertension, cardiac arrhythmia requiring medication, or baseline corrected QT by Fridericia's formula (QTcF) length > 470 msec for men and women. The QTcF cut-off value may be modified with supporting data for specific drug regimens. GEC6: CNS tumoral spread: Active uncontrolled/symptomatic central nervous system cancer/spinal cord compression. Previously treated and clinically stable lesions, as per Investigator's judgment, are permitted. GEC7: Liver disease: Patients with clinically significant history of liver disease, including viral or other known hepatitis, current alcohol abuse, or cirrhosis. GEC8: Recent major surgery within 4 weeks prior to start IMP treatment GEC9: Pregnancy or breastfeeding GEC10: Individuals accommodated in an institution because of regulatory or legal order; prisoners or participants who are legally institutionalized. GEC11: Other conditions, which in the opinion of the investigator, would compromise the safety of the patient or the patient's ability to complete the study. Additional arm specific exclusion criteria as needed by drug arm regimen

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: Single Group Assignment
Interventional Model Description: This is an open-label, multi-site, multi-arm platform study, where each drug regimen arm may have different study designs and eligibility. In particular, dose finding parts may employ different designs (e.g., 3+3, Bayesian Optimal Interval Design [BOIN], continual reassessment method [CRM], etc.) for each arm in the PRE-I-SPY program. See each arm for specific study model details.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PRE1 ALX148 (Evorpacept) + Fam-Trastuzumab Deruxtecan-Nxki (T-DXd, Enhertu®)<br>The combination of T-DXd and ALX148 aims to explore the anti-tumoral effects of trastuzumab, of the topoisomerase inhibitor DXd and of the CD47-blocking agent ALX148. The rationale for this combination is that ALX148 is hypothesized, based on preclinical data, to facilitate antibody-dependent cellular phagocytosis (ADCP) of HER2 expressing (>HER2 1+) breast cancer binding T-DXd while cancer cell intrinsic or bystander cytotoxicity of T-DXd will result in the release of neoantigens promoting immune mediated antitumor activity in the tumor microenvironment. | Drug: ALX148<br>* CD47 Inhibitor: A fusion protein containing a high affinity engineered D1 domain of human signal regulatory protein alpha (SIRPα) variant 1 (v1) genetically linked to a modified and inactive Fc domain of human immunoglobulin (Ig) G1.<br>* Other names: Evorpacept;Drug: Fam-Trastuzumab Deruxtecan-Nxki<br>* Antibody-drug conjugate (ADC): A recombinant humanized anti-human HER2 IgG1 monoclonal antibody, conjugated with linker to a Topoisomerase I inhibitor<br>* Other names: T-DXd;|
| Experimental: PRE2 Zanidatamab (ZW25, zani) + Tucatinib (TUKYSA®)<br>Zanidatamab is a bispecific IgG1-like antibody directed against two distinct HER2 epitopes. It induces formation of receptor clusters and internalization resulting in downregulation. It also inhibits growth factor-dependent and -independent tumor cell proliferation as well as potently activating ADCC, ADCP, and CDC. Tucatinib is a highly selective, small molecule tyrosine kinase inhibitor (TKI) of HER2 compared to other TKI's (i.e., EGFR). It is well tolerated, crosses the blood brain barrier and can treat CNS disease. It is FDA approved for HER2+ breast cancer. Given the promising clinical data for each of these drugs which have different mechanisms, the effect of zanidatamab after T-DXd (Enhertu®) in breast cancer patients, and the favorable toxicity profile of both drugs, we hypothesize that the combination of tucatinib and zanidatamab will be well tolerated and more efficacious than either drug alone for the treatment of patients with HER2 positive breast cancer. | Drug: Zanidatamab<br>* Bispecific HER2 antibody: A humanized, bispecific, immunoglobulin G isotype 1 (IgG1)-like antibody directed against the juxtamembrane extracellular domain (ECD4) and the dimerization domain (ECD2) of human epidermal growth factor receptor 2 (HER2).<br>* Other names: zani;Drug: Tucatinib<br>* Small molecule tyrosine kinase inhibitor (TKI) of HER2 (oral drug).<br>* Other names: TUKYSA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events related to the treatment | Evaluate the number of adverse events related to the treatment according to the current version of CTCAE during the trial. | Start of treatment to 30 days post treatment (estimated 12 -18 months) | 
| Incidence of Dose Limiting Toxicities (DLTs) at each dose level | To determine the safety and tolerability of new agents/regimens in participants with certain advanced solid tumors and breast cancer. DLT rate (number of participants who experience a protocol defined DLT/total number of DLT cohort participants at that dose). | DLT observation period: Start of treatment to 21 days (Cycle 1) | 
| Maximum Tolerated Dose (MTD) | The maximum dose level (mg/kg) which is not eliminated. | Start of treatment to the date of last participant at end of DLT observation period at highest dose level (estimated 6 months) | 
| Recommended Phase 2 Dose (RP2D) | Using all available data, computation of RP2D (mg/kg), which may not be the MTD. | Start of treatment to the date of last participant at highest dose level (estimated 6 months) | 
| Overall Response Rate (ORR) | To obtain preliminary efficacy data of the new agents/regimens in participants with certain advanced solid tumors and breast cancer. | Start of treatment to 12 months | 
| Duration of Response (DOR) | To obtain preliminary efficacy data of the new agents/regimens in participants with certain advanced solid tumors and breast cancer. | Start of treatment to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) - descriptive | To provide descriptive assessment of Progression Free Survival (PFS) of the new agents/regimens with certain advanced solid tumors and breast cancer | Start of treatment to 12 months | 
| Clinical Benefit Rate (CBR) at 6 months | To obtain preliminary Clinical Benefit Rate (CBR) at 6 months of participants treated with the new agents/regimens. | Start of treatment to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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QLHC, I-SPY Trials, Quantum Leap Healthcare Collaborative, I-SPY, I-SPY2, I-SPY1, PRE-ISPY, PRE-I-SPY, I-SPY Phase 1, I-SPY Phase 1b, I-SPY-P1, ISPY, ISPYP1, I-SPY Phase 1 Platform, ISPY2, ISPY1, Phase 1 Platform, Phase 1 Oncology Platform, T-DXd naive, PRE1, PRE2, PRE3