A Study of T-DXd for the Treatment of Solid Tumors Harboring HER2 Activating Mutations (DPT01)

• ClinicalTrials.gov Identifier: NCT04639219
• Recruitment Status: Active, not recruiting
• First Posted: November 20, 2020
• Results First Posted: February 15, 2024
• Last Update Posted: April 22, 2024
• Sponsor: AstraZeneca
• Collaborator: Daiichi Sankyo Co., Ltd.
• Information provided by (Responsible Party): AstraZeneca

Study Description

Brief Summary:

This is an open-label, multi-center, single arm, Phase II study to evaluate the efficacy and safety of T-DXd for the treatment of unresectable and/or metastatic solid tumors harboring specific HER2 activating mutations regardless of tumor histology. The target population are patients who have progressed following prior treatment or who have no satisfactory alternative treatment options, including approved second line therapies in the specific tumor type. Pre-specified HER2 mutations will be locally assessed using NGS tests or alternative methods. Prior HER2 targeting therapy is permitted.

Condition or disease	Intervention/treatment	Phase
Advanced Solid Tumors With HER2 Mutation,eg:Colorectal,Urothelial,Gastric, Hepatobiliary,Endometrial,Melanoma,Ovarian,Cervical,Salivary Gland,Pancreatic,Breast	Drug: Trastuzumab deruxtecan	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 102 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Masking Description: None (open-label)
• Primary Purpose: Treatment
• Official Title: A Phase II, Multicenter, Open-label Study to Evaluate the Efficacy and Safety of Trastuzumab Deruxtecan (T-DXd) for the Treatment of Unresectable and/or Metastatic Solid Tumors Harboring HER2 Activating Mutations Regardless of Tumor Histology
• Actual Study Start Date: December 30, 2020
• Actual Primary Completion Date: January 25, 2023
• Estimated Study Completion Date: July 14, 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: T-DXd; T-DXd monotherapy	Drug: Trastuzumab deruxtecan; Trastuzumab deruxtecan (T-DXd) by intravenous infusion; Other Name: DS-8201a (T-DXd)

Outcome Measures

Primary Outcome Measures :

1. Confirmed Overall Response Rate (ORR) as Per RECIST v1.1 Using Independent Central Review (ICR) [ Time Frame: Tumor scans performed at screening,then every 6 weeks (q6w) +/- 1 week relative to date of first treatment administration until RECIST v1.1 objective PD, withdrawal of consent, or death by any cause, up to DCO date of 25 Jan 2023 (approximately 24 months) ]
   Confirmed ORR was defined as the percentage of participants who had a confirmed complete response (CR) or partial response (PR), as determined by ICR per RECIST v1.1. A CR was defined as disappearance of all target lesions (TLs) and PR was defined as at least a 30% decrease in the sum of the diameters (dms) of TL, taking as reference the baseline sum of diameters as long as criteria for PD were not met. An ICR of all radiological imaging data was carried out using RECIST v1.1. All images were collected centrally. The imaging scans were reviewed by 2 independent radiologists and were adjudicated, if required.

Secondary Outcome Measures :

1. Duration of Response (DoR) as Per RECIST v1.1 Using ICR and Investigator Assessment [ Time Frame: Tumor scans performed at screening, then q6w +/- 1 week relative to the date of first treatment administration until RECIST v1.1 objective PD, withdrawal of consent, or death by any cause, up to DCO date of 25 Jan 2023 (approximately 24 months) ]
   DoR was defined as the time from the date of first documented response until date of documented progression or death in the absence of disease progression (date of progression-free survival [PFS] event or censoring - date of first response + 1). The DoR was calculated using Kaplan-Meier technique.
2. Disease Control Rate (DCR) as Per RECIST v1.1 Using ICR and Investigator Assessment [ Time Frame: Tumor scans performed at screening, then q6w +/- 1 week relative to the date of first treatment administration until RECIST v1.1 objective PD, withdrawal of consent, or death by any cause, up to DCO date of 25 Jan 2023 (approximately 24 months) ]
   DCR at 6 weeks was defined as the percentage of participants who had the best objective response (BoR) of confirmed CR or PR, or who had stable disease (SD) (without subsequent cancer therapy), for at least 5 weeks after first dose of study treatment. DCR at 12 weeks was defined as the percentage of patients who had the BoR of confirmed CR or PR, or who had SD (without subsequent cancer therapy), for at least 11 weeks after first dose of study treatment. CR was defined as disappearance of all TL and PR was defined as at least a 30% decrease in sum of the dms of TL, taking as reference the baseline sum of dms as long as criteria for PD were not met. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD (>=20% increase in sum of dms of TLs and an absolute increase of >=5 millimeters, taking as reference smallest sum of dms since treatment started including baseline sum of dms). CI was calculated using Clopper-Pearson method.
3. PFS as Per RECIST v1.1 Using ICR and Investigator Assessment [ Time Frame: Tumor scans performed at screening, then q6w +/- 1 week relative to the date of first treatment administration until RECIST v1.1 objective PD or death by any cause, up to DCO date of 25 Jan 2023 (approximately 24 months) ]
   PFS was defined as the time from first dose of study treatment until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdrew from assigned therapy or received another anti-cancer therapy prior to progression (i.e. date of PFS event or censoring - date of first dose + 1). PFS was calculated using the Kaplan-Meier technique. CI for median PFS derived based on the Brookmeyer-Crowley method.
4. Percentage of Participants Alive and Progression-Free at 6 and 12 Months as Per RECIST v1.1 Using ICR and Investigator Assessment [ Time Frame: At Months 6 and 12 ]
   Percentage of participants alive and progression-free at 6 and 12 months are reported. It was calculated using the Kaplan-Meier technique. CI for median PFS derived based on the Brookmeyer-Crowley method.
5. Confirmed ORR as Per RECIST v1.1 Using Investigator Assessment [ Time Frame: Tumor scans performed at screening, then q6w +/- 1 week relative to the date of first treatment administration until RECIST v1.1 objective PD, withdrawal of consent, or death by any cause, up to DCO date of 25 Jan 2023 (approximately 24 months) ]
   Confirmed ORR was defined as the percentage of participants who had a confirmed CR or PR as determined by investigator per RECIST v1.1. A CR was defined as disappearance of all TLs and PR was defined as >=30% decrease in the sum of the dms of TL, taking as reference the baseline sum of dms as long as criteria for PD were not met.
6. Overall Survival (OS) [ Time Frame: From the date of first treatment administration up to death, approximately 24 months ]
   OS was defined as the time from the date of first dose of study treatment administration until death due to any cause regardless of whether the patient withdrew from therapy or received another anti-cancer therapy (i.e. date of death or censoring - date of first dose + 1). OS was calculated using the Kaplan-Meier technique. CI for median OS derived based on the Brookmeyer-Crowley method.
7. Percentage of Participants Alive at 6 and 12 Months [ Time Frame: At Months 6 and 12 ]
   Percentage of participants alive at 6 and 12 months are reported. It was calculated using the Kaplan-Meier technique. CI for median PFS derived based on the Brookmeyer-Crowley method.
8. Serum Concentrations of T-DXd and Total Anti-HER2 Antibody [ Time Frame: Pre-infusion and 15 minutes post-infusion in Cycles 1, 2 and 4 and 5 hours post-infusion in Cycle 1 (each cycle 21 days) ]
   Serum samples were collected at specified timepoints to determine serum concentrations of T-DXd and total anti-HER2 antibody.
9. Serum Concentrations of Deruxtecan (MAAA-1181a) [ Time Frame: Pre-infusion and 15 minutes post-infusion in Cycles 1, 2 and 4 and 5 hours post-infusion in Cycle 1 (each cycle 21 days) ]
   Serum samples were collected at specified timepoints to determine serum concentrations of MAAA-1181a.
10. Percentage of Participants With Anti-Drug Antibodies (ADA) to T-DXd [ Time Frame: Up to approximately 24 months ]
    Blood samples were collected to evaluate the presence of ADAs for T-DXd using validated assays. ADA prevalence was defined as the percentage of participants with positive ADA result at any time, baseline or post-baseline. ADA incidence was defined as the percentage of participants who were evaluable for ADA and were treatment-emergent ADA-positive. Treatment-emergent ADA was defined as either treatment-induced (baseline ADA negative, post-baseline ADA positive) or treatment-boosted ADA. Treatment-boosted ADA was defined as baseline positive ADA titer that was boosted to >=2 fold during the study period. Persistently positive was defined as >=2 post-baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. Transiently positive was defined as having >=1 post baseline ADA positive measurement and not fulfilling the conditions for persistently positive.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 120 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Adults ≥18 years old. Other age restrictions may apply as per local regulations.
• Unresectable and/or metastatic solid tumors with pre-specified HER2 mutations (S310F, S310Y, G660D, R678Q, D769Y, D769H, V777L, Y772_A775dup / A775_G776insYVMA, L755S, G778_P780dup / P780_Y781insGSP, T862A, and V842I locally determined by NGS or a validated nucleic acid-based methodology (eg, qPCR, digital PCR) on tumor tissue, who have progressed following prior treatment or who have no satisfactory alternative treatment options.
• Prior HER2 targeted therapy is permitted.
• All patients must provide an FFPE tumor sample for retrospective central HER2 testing.
• LVEF ≥50%
• ECOG 0-1
• All patients have measurable target disease assessed by the Investigator based on RECIST v1.1

Exclusion Criteria:

• HER2 overexpressing (IHC3+ or IHC2+/ISH+) breast, gastric or gastroesophageal junction adenocarcinoma.
• HER2 mutant NSCLC.
• Medical history of myocardial infarction within 6 months before randomization/enrolment, symptomatic CHF, unstable angina pectoris, clinically important cardiac arrhythmias, or a recent (< 6 months) cardiovascular event including stroke.
• History of non-infectious pneumonitis/ILD, current ILD, or where suspected ILD cannot be ruled out by imaging at screening
• Corrected QT interval by Fridericia's formula (QTcF) prolongation to > 470 msec (females) or > 450 msec (males) based on average of the screening triplicate 12-lead ECG.
• Lung-specific intercurrent clinically significant severe illnesses.
• History of active primary immunodeficiency, known HIV, active HBV or HCV infection
• Uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals
• Pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART).
• Has spinal cord compression or clinically active central nervous system metastases.

Contacts and Locations

Locations

United States, California

Research Site

Santa Rosa, California, United States, 95403

United States, Indiana

Research Site

Muncie, Indiana, United States, 47303

United States, Massachusetts

Research Site

Boston, Massachusetts, United States, 02115

Research Site

Boston, Massachusetts, United States, 02215

United States, New Jersey

Research Site

Middletown, New Jersey, United States, 07748

United States, New York

Research Site

Commack, New York, United States, 11725

Research Site

Harrison, New York, United States, 10604

Research Site

New York, New York, United States, 10021

United States, Texas

Research Site

Houston, Texas, United States, 77030

United States, Virginia

Research Site

Fairfax, Virginia, United States, 22031

Belgium

Research Site

Anderlecht, Belgium, 1070

Canada, CA

Research Site

Toronto, CA, Canada, M5G 2M9

Denmark

Research Site

Copenhagen, Denmark, 2100

France

Research Site

Bordeaux, France, 33076

Research Site

Lyon Cedex 08, France, 69008

Research Site

Villejuif Cedex, France, 94805

Italy

Research Site

Milano, Italy, 20162

Research Site

Milan, Italy, 20141

Research Site

Napoli, Italy, 80131

Japan

Research Site

Chuo-ku, Japan, 104-0045

Research Site

Kashiwa, Japan, 277-8577

Research Site

Suita-shi, Japan, 565-0871

Korea, Republic of

Research Site

Seoul, Korea, Republic of, 03080

Research Site

Seoul, Korea, Republic of, 03722

Research Site

Seoul, Korea, Republic of, 06351

Spain

Research Site

Barcelona, Spain, 08035

Research Site

Madrid, Spain, 28041

Research Site

Madrid, Spain, 28050

Research Site

Pamplona, Spain, 31008

Research Site

Sevilla, Spain, 41013

Sponsors and Collaborators

AstraZeneca

Daiichi Sankyo Co., Ltd.

  Study Documents (Full-Text)

Documents provided by AstraZeneca:

Study Protocol  [PDF] July 20, 2020

Statistical Analysis Plan  [PDF] February 7, 2023

More Information

Additional Information:

Redacted CSR synopsis 

Redacted SAP 

Redacted CSP 

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT04639219
• Other Study ID Numbers: D967MC00001; 2020-002368-30 ( EudraCT Number )
• First Posted: November 20, 2020
• Results First Posted: February 15, 2024
• Last Update Posted: April 22, 2024
• Last Verified: April 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Access Criteria

When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool .

Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access.

For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by AstraZeneca:

HER2; T-DXd; DS-8201a; Trastuzumab Deruxtecan; Metastatic; Solid Tumors; Histology Agnostic

Additional relevant MeSH terms:

Neoplasms; Trastuzumab; Trastuzumab deruxtecan; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunoconjugates; Immunologic Factors; Physiological Effects of Drugs