Lead Investigator: Andreas Meid, Heidelberg University Hospital
Title of Proposal Research: MAGIC-BULLET – Model-based support of translational steps throughout drug development of antibody-drug conjugates (ADCs) in breast cancer
Vivli Data Request: 9229
Funding Source: Andreas D. Meid is personally funded by the Sanofi iTech Awards Program.
Potential Conflicts of Interest: Dr. Meid reports: This is a pure research project with no commercial interests. There are no conflicts of interest with the lead researcher/statistician Andreas D. Meid. Andreas D. Meid is personally funded by the Sanofi iTech Awards Program for a project developing a translational model to predict the ADC pharmacokinetics and pharmacodynamics (PD) of n e w ADCs. These differ from the ADCs studied here, which can serve as proof-of-concept for the fundamental approach of model-informed decision making. Although one can always learn from earlier data or literature, there is no direct link to other substances.
Dr. Leiva-Escobar reports: As a potential PhD candidate, Ignacio Leiva-Escobar will be involved in this pure research project with no commercial interests. There are no conflicts of interest with the additional researcher.
Summary of the Proposed Research:
Breast cancer was the most common type of cancer among females in developing and developed countries in 2020. Subtypes of breast cancers can be classified by the expression of certain proteins. Human epidermal growth factor receptor 2 (HER2) is such a protein involved in normal cell growth. However, larger than normal amounts of HER2, promote the growth of cancer cells. The HER2-positive subtype accounts for approximately 20% of all breast cancers and has always been considered one of the most aggressive cancers with the worst prognosis if left untreated. However, as new treatment options could specifically target HER2, we have observed just the opposite, namely a better prognosis in cases treated with such drugs. Treatment with HER2-directed drugs has become the usual treatment for women with early breast cancer. These drugs, especially if wisely chosen for the particular patient, will become even more important worldwide because we observed approximately 2.3 million new cases in 2020 and see a predicted annual increase of over 3 million new cases by 2040.
The first HER2-directed drugs were antibodies. However, tumors can become resistant (less/not susceptible) to them limiting their efficacy. In the last decade, a new drug class called antibody-drug conjugates (ADCs) was developed. ADCs are targeted drugs that deliver chemotherapy agents to cancer cells. As usual in clinical development, many ADCs failed to prove their benefit. Successful ADCs have shown an overall increased benefit within clinical trial populations (e.g. prolonged time to cancer recurrence). Nevertheless, this benefit can vary from person to person and may be influenced by a person’s characteristics. Therefore, using the summary results of these clinical trials in clinical practice is challenging.
Against this background, decision makers in clinical development or in routine patient care could be supported by recommendations from (statistical) models. MAGIC-BULLET therefore develops statistical models to (1) predict the benefit of new drugs from preclinical experiments to clinical trials in humans and to (2) predict individual responses to already marketed drugs. While project goal (1) primarily adds value to clinical development of new drugs in the future, project goal (2) can potentially improve patient care with already available drugs.
Therefore, we consider two ADCs to demonstrate that (1) the (early) clinical response can be predicted from preclinical experiments and that (2) individualized treatment decisions in clinical practice can be derived from clinical trial data. For project goal (1), we extend existing models to predict ADC behavior in clinical trials. For project goal (2), we study how the individual response to the ADC depends on patient characteristics and how this could possibly be used (via a model) to derive individualized treatment recommendations. For this purpose, we apply several modeling options including, the creation of weighted clinical trial populations that resemble patients encountered in clinical practice or by using the clinical trial information to predict how individual patients may benefit based on their own characteristics
Requested Studies:
A Randomized, Multicenter, Phase ii Study of the Efficacy and Safety of Trastuzumab-MCC-DM1 vs. Trastuzumab (Herceptin®) and Docetaxel (Taxotere®) in Patients With Metastatic HER2-positive Breast Cancer Who Have Not Received Prior Chemotherapy for Metastatic Disease
Data Contributor: Roche
Study ID: NCT00679341
Sponsor ID: BO21976
A Phase 2, Multicenter, Open-Label Study of DS-8201a, an Anti-HER2-Antibody Drug Conjugate (ADC) for HER2-Positive, Unresectable and/or Metastatic Breast Cancer Subjects Previously Treated With T-DM1 (DESTINY-Breast01)
Data Contributor: Daiichi Sankyo, Inc.
Study ID: NCT03248492
Sponsor ID: DS8201-A-U201
A Phase 1, Multicenter, Open-label, Single Sequence Crossover Study to Evaluate Drug-drug Interaction Potential of OATP1B/CYP3A Inhibitor on the Pharmacokinetics of DS-8201a in Subjects With HER2-expressing Advanced Solid Malignant Tumors
Data Contributor: Daiichi Sankyo, Inc.
Study ID: NCT03383692
Sponsor ID: DS8201-A-A104
A Randomized, Multicenter, Phase III Open-label Study of the Efficacy and Safety of Trastuzumab MCC-DM1 vs. Capecitabine + Lapatinib in Patients With HER2-Positive Locally Advanced or Metastatic Breast Cancer Who Have Received Prior Trastuzumab-Based Therapy
Data Contributor: Roche
Study ID: NCT00829166
Sponsor ID: BO21977
A Phase III Randomized, Multicenter, Two Arm, Open-label Trial to Evaluate the Efficacy of Trastuzumab Emtansine Compared With Treatment of Physician’s Choice in Patients With HER2-positive Metastatic Breast Cancer Who Have Received at Least Two Prior Regimens of HER2 Directed Therapy
Data Contributor: Roche
Study ID: NCT01419197
Sponsor ID: BO25734
A Randomized, Multicenter, Open-Label Phase III Study to Evaluate the Efficacy and Safety of Trastuzumab Emtansine Versus Trastuzumab as Adjuvant Therapy for Patients With HER2-Positive Primary Breast Cancer Who Have Residual Tumor Present Pathologically in the Breast or Axillary Lymph Nodes Following Preoperative Therapy
Data Contributor: Roche
Study ID: NCT01772472
Sponsor ID: BO27938
A Randomized, Multicenter, Open-Label, Two-Arm, Phase III Neoadjuvant Study Evaluating Trastuzumab Emtansine Plus Pertuzumab Compared With Chemotherapy Plus Trastuzumab and Pertuzumab for Patients With HER2-Positive Breast Cancer
Data Contributor: Roche
Study ID: NCT02131064
Sponsor ID: BO28408
A Randomized, Multicenter, Open-Label, Phase III Trial Comparing Trastuzumab Plus Pertuzumab Plus a Taxane Following Anthracyclines Versus Trastuzumab Emtansine Plus Pertuzumab Following Anthracyclines as Adjuvant Therapy in Patients With Operable HER2-Positive Primary Breast Cancer
Data Contributor: Roche
Study ID: NCT01966471
Sponsor ID: BO28407
A Randomized, 3 Arm, Multicenter, Phase III Study to Evaluate the Efficacy and the Safety of T-DM1 Combined With Pertuzumab or T-DM1 Combined With Pertuzumab-Placebo (Blinded for Pertuzumab), Versus the Combination of Trastuzumab Plus Taxane, as First Line Treatment in HER2 Positive Progressive or Recurrent Locally Advanced or Metastatic Breast Cancer
Data Contributor: Roche
Study ID: NCT01120184
Sponsor ID: BO22589
A Phase II, Single-arm, Open-label Study of Trastuzumab-MCC-DM1 Administered Intravenously to Patients With HER2-Positive Metastatic Breast Cancer Who Have Progressed While Receiving HER2-Directed Therapy
Data Contributor: Roche
Study ID: NCT00509769
Sponsor ID: TDM4258g
A Phase II, Open-Label Study to Evaluate Corrected QT Interval Effects of Trastuzumab-MCC-DM1 (T-DM1) in Patients With HER2-Positive Locally Advanced or Metastatic Breast Cancer and to Evaluate the Safety and Tolerability of Combined T-DM1 and Pertuzumab in Patients With Early Disease Progression While Receiving T-DM1 Alone
Data Contributor: Roche
Study ID: NCT00943670
Sponsor ID: TDM4688g
A Phase II, Single-Arm, Open-Label Study of Trastuzumab-Mcc-DM1 Administered Intravenously to Patients With HER2-Positive Metastatic Breast Cancer
Data Contributor: Roche
Study ID: NCT00679211
Sponsor ID: TDM4374g
A Two-Cohort, Open-Label, Multicenter Study of Trastuzumab Emtansine (T-DM1) in HER2-Positive Locally Advanced or Metastatic Breast Cancer Patients Who Have Received Prior Anti-HER2 and Chemotherapy-Based Treatment
Data Contributor: Roche
Study ID: NCT01702571
Sponsor ID: MO28231