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Trastuzumab

Trastuzumab deruxtecan

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Patients receive trastuzumab deruxtecan IV over 30-90 minutes on day 1 and ceralasertib PO BID on days 1-7. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. NOTE: During the dose-expansion phase, the first 6 patients in each disease cohort (gastroesophageal cancer \[cohort A\] and colorectal cancer \[cohort B\]) receive only trastuzumab deruxtecan for the first cycle, followed by trastuzumab deruxtecan and ceralasertib together in subsequent cycles.

Ceralasertib

Trastuzumab Deruxtecan

Site Public Contact

Heinz-Josef Lenz

Farshid Dayyani

Jonathan W. Riess

Jibran Ahmed

Patrick Grierson

Despina Siolas

Susanna V. Ulahannan

Babar Bashir

Kyaw L. Aung

Syed M. Kazmi

Kanwal P. Raghav

Vaia Florou

Kanwal P Raghav

The dose escalation phase of this trial identifies the best dose and safety of ceralasertib (AZD6738) when given in combination with trastuzumab deruxtecan (DS-8201a) in treating patients with solid tumors that have a change (mutation) in the HER2 gene or protein and have spread to other places in the body (advanced). The dose expansion phase (phase Ib) of this trial compares how colorectal and gastroesophageal cancers with HER2 mutation respond to treatment with a combination of ceralasertib and trastuzumab deruxtecan versus trastuzumab deruxtecan alone. Trastuzumab deruxtecan is a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called deruxtecan. Trastuzumab attaches to HER2 positive cancer cells in a targeted way and delivers deruxtecan to kill them. Ceralasertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. Evaluate safety, tolerability, and recommended phase 2 dose (RP2D) of trastuzumab deruxtecan (DS-8201a) in combination with ceralasertib (AZD6738) in advanced solid tumors with HER2 expression. (Escalation Phase) II. Assess differential pharmacodynamic (PD) profile of tumor tissue (deoxyribonucleic acid \[DNA\] damage \& repair) between Top1 inhibition and dual inhibition of Top1 and ATR in patients with colorectal cancer and gastroesophageal cancer with HER2 expression. (Expansion Phase)

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. II. To evaluate pharmacokinetics (PK) of DS-8201a and AZD6738 and immunogenicity of DS8201a.

EXPLORATORY OBJECTIVES:

I. Evaluate association between HER2 heterogeneity and response to DS-8201a plus (+) AZD6738 therapy using central protein expression assessment.

II. Determine predictive biomarkers (including but not restricted to: HER2 protein levels, HER2 gene copy number, alterations of TP53, ATM and RAS) of DS-8201a + AZD6738 efficacy in advanced solid tumors (specifically colorectal cancer and gastroesophageal cancer) with HER2 expression.

III. To characterize PD biomarkers for efficacy of DS-8201a + AZD6738 efficacy in advanced solid tumors (specifically colorectal cancer and gastroesophageal cancer) with HER2 expression (such as phosphorylated \[p\]RAD50 and SLFN11).

IV. To establish a biorepository of tissue, blood and pre-clinical models (PDXs) for HER2 expressing advanced solid tumors (specifically colorectal cancer and gastroesophageal cancer).

OUTLINE: This is a dose-escalation study of ceralasertib with fixed dose trastuzumab deruxtecan followed by a dose-expansion study.

Patients receive trastuzumab deruxtecan intravenously (IV) over 30-90 minutes on day 1 and ceralasertib orally (PO) twice daily (BID) on days 1-7. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. NOTE: During the dose-expansion phase, the first 6 patients in each disease cohort (gastroesophageal cancer \[cohort A\] and colorectal cancer \[cohort B\]) receive only trastuzumab deruxtecan for the first cycle, followed by trastuzumab deruxtecan and ceralasertib together in subsequent cycles.

After completion of study treatment, patients are followed up every 3 months for 2 years, then every 6 months for 3 years.

Testing the Combination of Two Anti-cancer Drugs, DS-8201a and AZD6738, for The Treatment of Patients With Advanced Solid Tumors Expressing the HER2 Protein or Gene, The DASH Trial

Phase 1/1B Study of DS-8201a in Combination With ATR Inhibition (AZD6738) in Advanced Solid Tumors With HER2 Expression (DASH Trial)

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Chi-squared tests/Fisher-exact test will be used to study these associations.

The descriptions and grading scales found in the revised National Cancer institute Common Terminology Criteria for Adverse Events version 5.0 will be utilized for adverse event reporting.

Will be determined based on the totality of safety, clinical activity, and pharmacokinetic data.

Will assess differential PD profile of tumor tissue between Top1 inhibition and dual inhibition of Top1 and ATR.

Assessed by Response Evaluation Criteria in Solid Tumors 1.1 criteria.

For each cohort the ORR and its 95% exact confidence interval will be estimated using the Clopper and Pearson Method.

Will compare PD markers between the groups. Descriptive statistics will be used.

National Cancer Institute (NCI)

Spots Global Cancer Trial Database for advanced colon carcinoma