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

Sponsor

QuantumLeap Healthcare Collaborative (Other)

Overall Status

Recruiting

CT.gov ID

NCT05868226

Collaborator

(none)

Enrollment

Locations

Arm

60.3

Anticipated Duration (Months)

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: ALX148 Drug: Fam-Trastuzumab Deruxtecan-Nxki	Phase 1

Detailed 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 months.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention 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 [CRB], etc.) for each arm in the PRE-I-SPY program. See each arm for specific study model details.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 [CRB], etc.) for each arm in the PRE-I-SPY program. See each arm for specific study model details.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Dec 22, 2022

Anticipated Primary Completion Date :

Dec 30, 2026

Anticipated Study Completion Date :

Dec 30, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: PRE1 ALX148 (Evorpacept) + Fam-Trastuzumab Deruxtecan-Nxki (T-DXd, Enhertu®) 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 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 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. Other Names: Evorpacept Drug: Fam-Trastuzumab Deruxtecan-Nxki Antibody-drug conjugate (ADC): Recombinant humanized anti-human HER2 IgG1 monoclonal antibody, conjugated with linker to a Topoisomerase I inhibitor Other Names: Enhertu T-DXd

Arm

Intervention/Treatment

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

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 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

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.

Other Names:

Evorpacept

Drug: Fam-Trastuzumab Deruxtecan-Nxki

Antibody-drug conjugate (ADC): Recombinant humanized anti-human HER2 IgG1 monoclonal antibody, conjugated with linker to a Topoisomerase I inhibitor

Other Names:

Enhertu

T-DXd

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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
Serum creatinine within normal institutional limits or estimated creatinine clearance ≥ 50 mL/min/1.73 m2 for patients with serum creatinine levels above institutional ULN.
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 and surgery, to grade ≤1 and neuropathy to grade ≤2 (except toxicities not considered a safety risk for the patient).
GIC10: Participant compliance: Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
GIC11: Full COVID-19 vaccination (verified by COVID vaccine card or medical record): will be required per published CDC guidelines on the day of consent.
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 3 weeks
investigational agents, 3 weeks or 5x drug elimination half-lives, whichever is greater
mitomycin C and nitrosoureas, 6 weeks
radiotherapy, 3 weeks
targeted therapy and endocrine 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. Prior mild infusion-related reactions that did not lead to drug discontinuation are allowed.
GEC4: Currently uncontrolled intercurrent illness including (active infection, diabetes, hypertension, pulmonary embolism, 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, cardiac arrhythmia requiring IV medication, or baseline corrected QT by Fridericia's formula (QTcF) length ≥ 450 ms for men and ≥ 470 ms for women.
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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The University of Chicago Medicine Comprehensive Cancer Center	Chicago	Illinois	United States	60637
2	University of Minnesota Masonic Cancer Center	Minneapolis	Minnesota	United States	55455