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Enrolled Subjects will receive a single-dose of DB-1303 at Dose Level 1 on Day 1 of each cycle Q3W

Enrolled Subjects will receive a single-dose of DB-1303 at Dose Level 2 on Day 1 of each cycle Q3W

Enrolled Subjects will receive a single-dose of DB-1303 at Dose Level 3 on Day 1 of each cycle Q3W

Enrolled Subjects will receive a single-dose of DB-1303 at Dose Level 4 on Day 1 of each cycle Q3W

Enrolled Subjects will receive a single-dose of DB-1303 at Dose Level 5 on Day 1 of each cycle Q3W

Enrolled Subjects will be randomized to receive a single-dose of DB-1303 on a selected dose level 1 or dose level 2 Day 1 of each cycle Q3W

Enrolled Subjects will receive a single-dose of DB-1303 on a selected dose level (RP2D) Day 1 of each cycle Q3W

Enrolled Subjects will receive a single-dose of DB-1303 at Dose Level 6 on Day 1 of each cycle Q3W

Enrolled Subjects will receive a single-dose of DB-1303 at Dose Level 7 on Day 1 of each cycle Q3W

Enrolled Subjects will be randomized to receive a single-dose of DB-1303 on a selected dose level 1 or dose level 2 on Day 1 of each cycle Q3W

Enrolled Subjects will receive a single-dose of DB-1303 on a selected dose level (RP2D) Day 1 of each cycle Q3W along with ritonavir and itraconazole to assess the DDI potential

Enrolled Subjects will receive a single-dose of DB-1303 on a selected dose level 1 or dose level 2 in combination with Pertuzumab on Day 1 of each cycle Q3W

DB-1303

Pertuzumab Injection

Britney Winterberger

This is a dose-escalation and dose-expansion Phase 1/2a trial to evaluate the safety and tolerability of DB-1303 in subjects with advanced solid tumors that express HER2.

This is a multicenter, non-randomized, open-label, multiple-dose, FIH study. The study consists of two parts: Part 1 adopts an accelerated titration at first dose level followed with classic "3+3" design to identify the MTD/RP2D; Part 2 is a dose expansion phase to confirm the safety, tolerability and explore efficacy in selected malignant solid tumors at the MTD/the RP2D. This study will enroll subjects with advanced/unresectable, recurrent, or metastatic HER2-expressing malignant solid tumors.

A Study of DB-1303 in Advanced/Metastatic Solid Tumors

A Phase 1/2a, Multicenter, Open-Label, First in Human Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of DB-1303 in Patients With Advanced/Metastatic Solid Tumors

Percentage of participants in Part 1 with DLTs

Percentage of participants with AEs in Part 1 graded according to NCI CTCAE v5.0

Percentage of Participants with SAEs in Part 1 graded according to NCI CTCAE v5.0

RP2D of DB-1303 based on the data collected during Part 1

Percentage of participants with AEs in Part 2 graded according to NCI CTCAE v5.0

Percentage of participants with SAEs in Part 2 graded according to NCI CTCAE v5.0

The percentage of subjects who had a best response rating of CR and PR, for Part 2 only which was maintained ≥4 weeks.

Area under the concentration-time curve from time 0 to infinity of DB-1303

Maximum observed plasma concentration (Cmax) of DB-1303

Data gathered from blood to determine Levels of anti-drug antibody (ADA) against DB 1303 in serum compared to baseline.

Proportion of participants who had a best response rating of CR or PR, or SD using RECIST V1.1.

The duration of time from date of first CR or PR to date of progressive disease or death due to any cause, whichever comes first using RECIST V1.1

The duration of time when receiving the first dose of study drug to the first date that is evaluated as either CR or PR using RECIST V1.1

The duration of time from participant receiving first dose of study drug to the last dose + 21 days

The percent change in the participant's target lesions from baseline to last study scan using RECIST V1.1

Time from subject receiving the first dose to disease progression or death by any cause

Time from subject receiving the first dose to death by any cause

DualityBio Inc.

Triple Negative Breast Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Breast Diseases

Skin Diseases

Amino Acids

Antibodies

Antibodies, Monoclonal

Trastuzumab

Trastuzumab deruxtecan

Immunoglobulins

Immunoglobulin G

Mitogens

Tyrosine Kinase Inhibitors

Immunoglobulins, Intravenous

Tucatinib

Topoisomerase I Inhibitors

Immunoconjugates

Immunologic Factors

Protein Kinase Inhibitors

Tyrosine

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.

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.

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.

ALX148

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

Fam-Trastuzumab Deruxtecan-Nxki

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).

Zanidatamab

Small molecule tyrosine kinase inhibitor (TKI) of HER2 (oral drug).

Smita M Asare

Maria Pitsiouni, PhD

Clara Duarte

Yordanos Tafesse

Nan Chen, MD

Rita Nanda, MD

Katie Vaughn, RN

Jessica Hellmer

David Potter, MD, PhD

Doug Yee, MD

Heather Walker

Julia Moore, RN

Paula Pohlmann, MD, MSc, PhD

Debasish Tripathy, MD

Paula R Pohlmann, MD, MSc, PhD

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.

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.

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.

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

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

Evaluate the number of adverse events related to the treatment according to the current version of CTCAE during the trial.

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).

The maximum dose level (mg/kg) which is not eliminated.

Using all available data, computation of RP2D (mg/kg), which may not be the MTD.

To obtain preliminary efficacy data of the new agents/regimens in participants with certain advanced solid tumors and breast cancer.

To provide descriptive assessment of Progression Free Survival (PFS) of the new agents/regimens with certain advanced solid tumors and breast cancer

To obtain preliminary Clinical Benefit Rate (CBR) at 6 months of participants treated with the new agents/regimens.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of DB-1303 in Advanced/Metastatic Solid Tumors	NCT05150691	HER2-positive A...	DB-1303 Pertuzumab Inje... Ritonavir Itraconazole	18 Years -	DualityBio Inc.
A Study of DB-1303 in Advanced/Metastatic Solid Tumors	NCT05150691	HER2-positive A...	DB-1303 Pertuzumab Inje... Ritonavir Itraconazole	18 Years -	DualityBio Inc.
PRE-I-SPY Phase I/Ib Oncology Platform Program	NCT05868226	HER2-positive B... Metastatic Canc... Metastatic Brea... Metastatic HER2-positive M... HER2 Mutation-R... HER-2 Protein O... HER2-negative B... Triple Negative... HR Positive Hormone Recepto... Estrogen Recept... Progesterone Re... Hormone Recepto... Solid Tumor Solid Tumor, Ad... Solid Carcinoma HER2 Low Breast... HER2 Low Breast... ER Positive Bre... PR-positive Bre...	ALX148 Fam-Trastuzumab... Zanidatamab Tucatinib	18 Years -	QuantumLeap Healthcare Collaborative

Spots Global Cancer Trial Database for her2 low breast cancer