PRE-I-SPY Phase I/Ib Oncology Platform Program (PRE-I-SPY-PI)

QuantumLeap Healthcare Collaborative

Status and phase: Enrolling; Phase 1

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

Treatments: Drug: ALX148; Drug: Fam-Trastuzumab Deruxtecan-Nxki; Drug: Tucatinib; Drug: Zanidatamab

Study type: Interventional

Funder types: Other

Identifiers

NCT05868226

I-SPY-P1

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 124 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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. Newly discovered asymptomatic lesions that are not life threatening and do not require urgent local treatment to ensure patient safety, after consultation with study regimen chaperones, may be 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.

• GEC12: Concomitant malignancies: A diagnosis of a malignancy in the 2 years prior to starting study treatment other than the disease under study. Exceptions include indolent or definitively treated malignancy not expected to require treatment during the study, affect the safety of subjects, or affect the endpoints of the trial.

• Additional arm specific exclusion criteria as needed by drug arm regimen

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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124 participants in 2 patient groups

PRE1 ALX148 (Evorpacept) + Fam-Trastuzumab Deruxtecan-Nxki (T-DXd, Enhertu®)

Experimental group

Description:

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.

Treatment:

Drug: Fam-Trastuzumab Deruxtecan-Nxki

Drug: ALX148

PRE2 Zanidatamab (Ziihera®, ZW25, zani) + Tucatinib (TUKYSA®)

Experimental group

Description:

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 and potently activates ADCC, ADCP, and CDC. FDA approved for metastatic HER2+ bile duct cancer. 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. 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 HER2+ breast cancer.

Treatment:

Drug: Zanidatamab

Drug: Tucatinib