Allarity Therapeutics, Inc. (NASDAQ:ALLR) informed investors of its progress with its portfolio of oncology drugs guided by its Drug Response Predictor (DRP) diagnostics in a pair of recently released press releases. In an update to its ongoing Phase II trials evaluating Ixempra and stenoparib, the company reports changes to its enrollment cut-off score and has adjusted dosing protocols. Allarity also dosed its first patient in its dovitinib and stenoparib combination trial which expects to benefit from synergistic anti-cancer activity.
Ixempra and Stenoparib Phase II Trial Updates
In a March 28, 2023 press release, Allarity announced updates to its Phase II programs that are evaluating Ixempra and stenoparib as monotherapies. The pace of recruitment for both trials has been slow due to impacts from the pandemic and from on-site personnel staffing. To address the issue, Allarity has engaged additional contract research organizations (CROs) to increase the number of trial sites. The protocols for both of the studies have also been modified so that a greater number of patients will qualify for enrollment.
The European Ixempra trial in metastatic breast cancer will see additional modifications from a trial protocol amendment that will reduce the Ixempra-drug response predictor (DRP) cut off score2 required before a patient may be enrolled. The score will be reduced from 67% to 33% in a change that is expected to increase the number of DRP-positive patients eligible to enroll.
The stenoparib trial in ovarian cancer will modify the dosing regimen from a once daily does to a bis in die (BID), or twice per day dosing. This is expected to produce more stable systematic drug levels throughout the treatment period. This change matches the dosing regimen that will be used in the Phase Ib combination study for stenoparib and dovitinib. An interim data readout from the study is expected in late 2023.
First Combination Patient Dosed
On March 20th, Allarity announced its first patient had been dosed in the Phase Ib combination study evaluating dovitinib and stenoparib in advanced solid tumors. In oncology, combination therapy has been found to be more effective than single-agent therapy due to a number of reasons that take advantage of multiple mechanisms of action. Primary benefits include the synergy of multiple drugs, overcoming resistance in single-agent therapy, improved efficacy and lower toxicity from lower individual dosing.
One of the primary tumors that will be examined is ovarian cancer which has been responsive to combination therapies including poly (ADP-ribose) polymerase (PARP) inhibitors, a class than includes stenoparib. PARP inhibitors are a targeted therapy used in cancer treatment, particularly for cancers with specific mutations in DNA repair genes. These mutations can retard DNA repair, leaving cancer cells more susceptible to damage. PARP is an enzyme that plays a role in repairing single-strand DNA breaks. PARP inhibitors block the activity of PARP, which prevents cancer cells from repairing single-strand DNA breaks. When cancer cells attempt to divide and replicate their DNA, this causes fatal double-strand DNA breaks, leading to cell death.
The other drug in the combination is dovitinib, a pan-tyrosine kinase inhibitor (TKI) that blocks the activity of tyrosine kinase enzymes. Tyrosine kinases can activate or deactivate various signaling pathways that control cell growth and division. An effective TKI can block tyrosine kinase enzymes which promote cancer cell growth and survival. This class of drug has shown effectiveness in a variety of liquid and solid tumors. Some TKIs are designed to target specific tyrosine kinase enzymes that are mutated or overexpressed while pan-TKIs, such as dovitinib, have broader activity against multiple tyrosine kinases. Dovitinib may also block the formation of new blood vessels that provide nutrients to tumors. It has anti-angiogenic properties that can complement other mechanisms of action. Anti-angiogenics inhibit signaling pathways for blood vessel formation, induce apoptosis and normalize blood vessel architecture in order to stop cancer.
The Phase Ib trial expects to enroll up to 36 patients with advanced solid tumors, focusing on specific tumor types anticipated to be most responsive to the drug combination. Researchers will analyze patient tumor samples in the context of stenoparib and dovitinib retrospectively using Allarity’s DRP precision medicine diagnostic in order to further validate DRP in advance of a DRP-guided Phase II trial. The study of the dovitinib and stenoparib combination in second line or later metastatic ovarian cancer is expected in 2H:24.
The rationale behind using a combination of agents is that the PARP inhibitor stenoparib will prevent the cancer cell’s ability to repair single stranded DNA breaks, which will lead to cancer cell death. The pan-TKI dovitinib can augment this mechanism of action by blocking the formation of blood vessels, thereby cutting off the nutrients that the cancer cells need to grow. It may also downregulate homologous recombination (HR) which prevents the repair of double strand breaks. The combination of these mechanisms is expected to have synergistic effects that may provide a significant progression free survival (PFS) benefit.3
Drug Response Predictor (DRP®) Platform
Allarity uses its Drug Response Predictor (DRP) platform to match the right patient with the right drug using genetic or molecular profiling. DRP takes into account an individual’s variability in genes, environment and lifestyle helping providers identify treatment and prevention approaches that are individually tailored. The platform will be used to determine a score and identify the patients best suited to be enrolled in the combination trial.
DRP provides a systematic approach to identify patients sensitive to a particular therapy. The primary steps in the process include:
➢ Evaluation of an established panel of cancer cell lines that have been treated with the candidate:
o The effort correlates the genetic expression profile of cell lines that are sensitive or resistant
o The NCI-60 panel is used to identify and characterize the effectiveness of novel compounds
o The impact of over 25,000 expressed genes is examined
➢ Identification of the specific mRNA & microRNA that are correlated with either response or resistance to that drug using DRP's bioinformatics algorithm
➢ Generation of a DRP companion diagnostic specific to the drug which identifies a subpopulation of cancer patients most likely to respond
➢ Validation of the DRP companion diagnostic using retrospective analysis.
In most cases, 50 to 100 biomarkers are sufficient to differentiate a tumor so that DRP can identify a drug as a matching candidate. The next step in the process is to validate the findings using retrospective data and to test the predictive capacity of the DRP. A cutoff score for patients is determined which optimizes the balance of favorable and unfavorable factors.
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1. March 2023 Allarity corporate presentation.
2. See page 6 of our initiation for a thorough description of the DRP platform and a discussion of the cutoff score.
3. Secord, A.A., et al. Rationale for combination PARP inhibitor and antiangiogenic treatment in advanced epithelial ovarian cancer: A review. Gynecologic Oncology, June 2021.
