As part of a new study focusing on advanced targeting human epidermal growth factor receptor-2 (HER2-) expressing cancers, including locally advanced or metastatic solid tumors, a first patient has started treatment with a combination of the investigational antibody-drug conjugate (ADC) [vic-]trastuzumab duocarmazine (SYD985; Byondis) in combination with the orally active small molecule PARP inhibitor (PARPi) niraparib (Zejula®; Tesaro/GSK).
The phase I study explores the preclinically proven synergistic anti-tumor effects of the trastuzumab duocarmazine and niraparib combination, which may result in increased efficacy.
In a statement, the investigators note that because both drugs are given at lower doses than when used as a single agent, the study combination could possibly lead to reduced toxicity. The two-part phase I study is expected to enroll up to 120 patients who progressed on standard therapy or for whom no standard therapy of proven benefit exists.
The study’s primary endpoint is dose-limiting toxicities in the first cycle (21 days). Secondary objectives include overall safety, pharmacokinetic, and preliminary efficacy assessments for the combination treatment.
The dose-escalation phase of the study is expected to enroll about 30 patients with any HER2-expressing solid tumor to determine the maximum tolerated dose (MTD) and the recommended dose for expansion (RDE). This part of the study is taking place in leading European oncology centers in Belgium, the United Kingdom, and the Netherlands. Leading centers in France, Spain, and Poland will join this trial at a later stage.
In the second phase, the dose-expansion part of the study, investigators expect to enroll between 48 and 90 patients with one of three types of locally advanced or metastatic cancers: breast, ovarian, or endometrial. All patients will be treated with trastuzumab duocarmazine infusions once every three weeks in combination with oral niraparib. The latter will be administered once daily for one, two, or three weeks, depending on the safety of the combination and the study cohort.
“We are excited to move to the clinical study phase of [vic-]trastuzumab duocarmazine in combination with PARP inhibitor niraparib,” noted Marco Timmers, Ph.D. Chief Executive Officer of Byondis.
“Preclinical investigation of SYD985 in combination with PARP inhibitors in HER2-expressing tumor cells suggested synergistic effects and we hope to confirm these effects in the clinic,” Timmers added.
Development program
Trastuzumab duocarmazine is an antibody-drug conjugate in development for the treatment of a range of HER2- expressing tumor types including breast and endometrial cancer. Previously, the U.S. Food & Drug Administration granted investigational drug fast track designation based on promising data from heavily pre-treated last-line HER2-positive metastatic breast cancer patients participating in a two-part Phase I clinical study. [1]
Other studies included the pivotal Phase III TULIP® study comparing the efficacy and safety of trastuzumab duocarmazine to physician’s choice treatment in patients with HER2-positive unresectable locally advanced or metastatic breast cancer is ongoing. In addition, Byondis recently announced the start of a Phase II study evaluating the safety and efficacy of trastuzumab duocarmazine in patients with HER2-expressing recurrent, advanced or metastatic endometrial (uterine) cancer.
Novel linker-drug technology
The antibody-part of the investigational drug has been used as a therapeutic agent (Herceptin®; Genentech/Roche). It is included as the targeting moiety in other antibody-drug conjugates, including ado-trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche) and fam-trastuzumab deruxtecan-nxki (DS-8201a; Enhertu®; Daiichi Sankyo and AstraZeneca). The trial drug uses Byondis’ proprietary cleavable linker-drug called valine-citrulline-seco-DUocarmycin-hydroxyBenzamide- Azaindole (vc-seco-DUBA) technology to link the targeting antibody (trastuzumab) to the cytotoxic agent.[2]
In traditional chemotherapy, a cytotoxin enters the bloodstream and moves through the body to kill rapidly dividing cells that are common in tumors. The problem is that it also attacks rapidly dividing cells in normal tissue, potentially resulting in severe side effects.
Antibodies are created to allow improved specificity by targeting receptors expressed on tumor cell membranes. In order to improve the cell-killing capability of antibodies, cytotoxic drugs can be attached to antibodies using a linker molecule, forming antibody-drug conjugates or ADCs.
The antibody part of trastuzumab duocarmazine binds to the HER2 antigen on the surface of the cancer cell and the ADC is internalized by the cell. After proteolytic cleavage of the linker, the inactive cytotoxin is activated and DNA damage is induced, resulting in tumor cell death.
Room for improvement
Over the last two decades, earlier generations of ADCs have improved therapeutic indices compared to classical non-targeted chemotherapeutic agents. There is, however, room for improvement.
While these earlier generations of antibody-drug conjugates improved targeting and tumor cell killing, they were often unstable in the bloodstream, which resulted in the early release of the cytotoxic payload, impacting healthy tissue, and narrowed the therapeutic window. To solve this problem, researchers working on the development of trastuzumab duocarmazine, have created an intricate, inactivated cytotoxic drug that rapidly self-destructs in case it is prematurely released, limiting damage to healthy tissue and improving the therapeutic window.
The differentiated linker-drug, vc-seco-DUBA, owes its potent antitumor activity to a synthetic duocarmycin-based cytotoxin. Duocarmycins, first isolated from Streptomyces bacteria in the 1970s, bind to the minor groove of DNA and disrupt the nucleic acid architecture, which eventually leads to tumor cell death.
The distinctive design of the selectively cleavable linker connecting the antibody to the duocarmycin drug leads to high stability in circulation and induces the efficient release of the cytotoxin in the tumor. Uptake of the activated payload by neighboring tumor cells with lower HER2 expression may improve the efficacy potential, the so-called bystander effect.
Trastuzumab duocarmazine kills tumor cells by causing DNA damage. Results of a previously conducted phase I study confirmed that the drug-induced partial responses in 33% of patients whose tumors were resistant to the approved antibody-drug conjugate trastuzumab emtansine. [3]
Combination
In the new clinical trial, investigators explore the combination of trastuzumab duocarmazine with the PARP inhibitor niraparib.
PARP inhibitors, used in ovarian, breast, prostate, and pancreatic cancer, are a type of targeted therapy designed to block critical DNA repair pathways that these cancers rely on to repair their DNA as they grow and divide, thereby inducing tumor cell death.
Investigators believe that combining the DNA-alkylating cytotoxic mechanism of trastuzumab duocarmazine with PARP inhibitors may increase the sensitivity of tumors for the cytotoxic payload of the trastuzumab duocarmazine, resulting in synergistic effects on tumor cell killing. The concept was confirmed in earlier, preclinical trials.
Clinical trials
Phase I Study of SYD985 With Niraparib in Patients With Solid Tumors – NCT04235101.
SYD985 in Patients With HER2-expressing Recurrent, Advanced or Metastatic Endometrial Carcinoma – NCT04205630
SYD985 vs. Physician’s Choice in Participants With HER2-positive Locally Advanced or Metastatic Breast Cancer (TULIP) – NCT03262935
First-in-human Study With the Antibody-drug Conjugate SYD985 to Evaluate Safety and Efficacy in Cancer Patients – NCT02277717
Highlights of prescribing information
Niraparib (Zejula®; Tesaro/GSK). [Prescribing Inform]
Trastuzumab (Herceptin®; Genentech/Roche) [Prescribing Inform]
Ado-trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche)[Prescribing Information]
Fam-trastuzumab deruxtecan-nxki (DS-8201a; Enhertu®; Daiichi Sankyo and AstraZeneca) [Prescribing Information]
References
[1] Banerji U, van Herpen CML, Saura C, et al. Trastuzumab duocarmazine in locally advanced and metastatic solid tumors and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study. Lancet Oncol. 2019;20(8):1124-1135. doi:10.1016/S1470-2045(19)30328-6
[2] Xu Z, Guo D, Jiang Z, et al. Novel HER2-Targeting Antibody-Drug Conjugates of Trastuzumab Beyond T-DM1 in Breast Cancer: Trastuzumab Deruxtecan(DS-8201a) and (Vic-)Trastuzumab Duocarmazine (SYD985). Eur J Med Chem. 2019;183:111682. doi:10.1016/j.ejmech.2019.111682
[3] New ADC Shrinks HER2-Positive Tumors. Cancer Discov. 2019;9(9):1151-1152. doi:10.1158/2159-8290.CD-NB2019-089
