PRE-ISPY Phase I/II Oncology Platform Program

QuantumLeap Healthcare Collaborative

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Solid Tumor; Colon Cancer; Colo-rectal Cancer; HER2 Low Breast Carcinoma; HER2-positive Breast Cancer; Adenocarcinoma; HER2-negative Breast Cancer; Minimal Residual Disease; Metastatic Cancer; Colonic Neoplasms; PR-positive Breast Cancer; Hormone Receptor Negative Breast Carcinoma; Progesterone Receptor-positive Breast Cancer; Estrogen Receptor Positive Tumor; Rectal Neoplasms; HER2 Mutation-Related Tumors; HER-2 Protein Overexpression; HER2 Low Breast Cancer; Solid Tumor, Adult; ctDNA Monitoring; HR Positive; HER2-positive Metastatic Breast Cancer; Neoplasm, Residual; Adenocarcinoma of Colon; ER Positive Breast Cancer; Hormone Receptor-positive Breast Cancer; Solid Carcinoma; Metastatic; Colorectal Neoplasms; Metastatic Breast Cancer; Triple Negative Breast Cancer; Rectal Cancer

Treatments: Drug: Fam-Trastuzumab Deruxtecan-Nxki; Drug: TTX-MC138; Drug: Zanidatamab; Drug: Tucatinib; Drug: ALX148

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT05868226

I-SPY-P1

Details and patient eligibility

About

PRE-ISPY Phase I/II (I-SPY-P1) is an open-label, multisite platform study with multiple ongoing drug regimen arms added by protocol amendment which is designed to evaluate single agents or combinations in locally advanced, incurable, or metastatic solid tumors and/or oligometastatic malignancy and/or a high risk of recurrence following prior treatment with curative intent. The overall goal is moving promising drug regimens into a larger phase II (or III) trial and in general could feed the neoadjuvant breast I-SPY 2 Trial (NCT01042379) and/or other oncology solid tumor trial in a timely manner.

Full description

The PRE-ISPY/I-SPY-P1 study is a platform trial with multiple ongoing drug regimen arms. Each drug regimen arm may have a Phase I dose-finding group (Part 1), a dose-expansion group (Part 2), and/or a Phase II component. Participant eligibility may vary according to the investigational arm or the part within the study arm, including with respect to diagnosis. Arms may restrict enrollment to a certain molecular pathway abnormality or histologic diagnosis (e.g. metastatic TNBC or MRD CRC). The trial allows for various study arm designs, with the goal to complete analysis of a study arm in 12 to 18 months.

Enrollment: 280 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 for research. If FFPE blocks cannot be submitted, 20 to 40 freshly cut FFPE tissue slices (4 to 7 microns thick each) from a representative FFPE block, mounted on charged glass slides and left unstained will be acceptable. This criteria can be modified in specific drug regimens.

• 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. This criteria can be modified in specific drug regimens.

• 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: Other anticancer therapy within the following period:

  • chemotherapy or investigational agents, 3 weeks
  • mitomycin C and nitrosoureas, 6 weeks
  • if radiotherapy is less than 5 days, 1 week wash out; if >5 days, then 2 weeks washout
  • for radionuclides, contact Study PI or Study Chaperone to determine washout
  • 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, adrenal insufficiency, pulmonary embolism, stroke 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. Exception: Newly discovered asymptomatic lesions that are not life threatening and do not require urgent local treatment to ensure patient safety, including new parenchymal lesions or leptomeningeal disease, if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy, after consultation with study regimen chaperones, may be permitted. This criteria can be modified in specific drug regimens.

• 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 participants, 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: Parallel Assignment

Masking: None (Open label)

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280 participants in 3 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: ALX148

Drug: Fam-Trastuzumab Deruxtecan-Nxki

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: Tucatinib

Drug: Zanidatamab

PRE4 TTX-MC138

Experimental group

Description:

TTX-MC138 is an antisense oligonucleotide targeting miR-10b. MicroRNA-10b (miR-10b) was identified in metastatic cell lines and tumors from participants with metastatic breast cancer and has been shown to regulate the ability of metastatic tumor cells to survive outside of the primary tumor and to migrate and invade surrounding tissue. miRNA-10b is critical to tumor growth and is a master regulator of metastatic cell viability in a range of cancers, including breast, pancreatic, ovarian, colon cancer, glioblast. This is a PRE-ISPY PHASE II study of TTX-MC138 as interception treatment in patients with Stage I-III adenocarcinoma of the colon or rectum (Cohort A) who have documented minimal residual disease by tumor informed ctDNA, that was collected following completion of standard therapy with curative intent.

Treatment:

Drug: TTX-MC138