On June 4, 2021 Cyteir Therapeutics, a leader in the discovery and development of next-generation synthetically lethal therapies for cancer, reported the presentation of an interim analysis of the Phase 1 portion of a first-in-human Phase 1/2 study of CYT-0851 (Press release, Cyteir Therapeutics, JUN 4, 2021, View Source [SID1234583544]). CYT-0851 is an oral, small molecule inhibitor of RAD51-mediated homologous recombination. The presentation was given at an oral session of the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) meeting.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The Phase 1 portion of the trial began enrolling patients with advanced hematologic cancers and solid tumors in September 2019. Patients were treated with continuous 28-day cycles of increasing oral doses of CYT-0851. The primary objective of the ongoing Phase 1 study is to identify the maximum tolerated dose (MTD). The key secondary objectives are evaluation of the safety, pharmacokinetics, and preliminary anti-tumor activity.

As of the April 6, 2021 data cutoff, 35 patients were treated with CYT-0851 across eight dose-escalation cohorts. Thirty-five patients were evaluable for safety and 21 patients were evaluable for efficacy. Patients had a median of four prior lines of therapy. Twenty-three patients discontinued treatment due to progressive disease (19), patient decision (2), physician decision (1) or adverse event (1). The adverse event that led to discontinuation was an increase in the aspartate aminotransferase (AST)/alanine aminotransferase (ALT) that was secondary to the patient’s cancer.

To date, CYT-0851 has been well-tolerated with 63% of patients reporting no treatment related adverse events. Thirteen patients (37.1%) experienced treatment-related adverse events with most events being low-grade. There have been no reported treatment-related Grade 4 or 5 events. The most common treatment-related adverse events were an increase in blood alkaline phosphatase levels (8.6%), fatigue (8.6%) and nausea (8.6%). There have been no reported dose-limiting toxicities, clinically significant myelosuppression, treatment discontinuations due to treatment-related adverse events, or treatment-related serious adverse events.

At the time of the data cutoff, there were 21 patients who were response evaluable. Three partial responses were observed in patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and soft tissue sarcoma. The patients with DLBCL and FL had confirmed responses according to Lugano criteria and the patient with sarcoma had a response that was unconfirmed according to RECIST. Ten patients had a best response of stable disease and four patients have been on therapy for more than six months, including the three patients that responded to treatment.

The study continues to dose-escalate to identify the MTD and enrollment is ongoing in the 400mg once daily dose cohort. Upon identification of the MTD, a Phase 2 dose will be selected, and the Phase 2 expansion cohorts are expected to begin enrollment in the second half of 2021.

On June 4, 2021 Phio Pharmaceuticals Corp. (Nasdaq: PHIO), a biotechnology company developing the next generation of immuno-oncology therapeutics based on its proprietary self-delivering RNAi (INTASYL) therapeutic platform, reported positive in vivo data that provide further evidence on the utility of its INTASYL self-delivering RNAi therapy platform in the field of immuno-oncology (Press release, Phio Pharmaceuticals, JUN 4, 2021, View Source [SID1234583561]). The new study data show how INTASYL can be easily deployed to target multiple proteins and provide evidence of the synergy of the Company’s pipeline products. In the study, INTASYL specifically dual-targeting BRD4 and PD-1 elicited complete tumor responses in an in vivo hepatoma model, and significantly outperformed the efficacy of small molecule and antibody treatments towards the same targets.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

In this study, the Company assessed the efficacy of mouse/human BRD4-targeting INTASYL PH-894 as monotherapy or co-formulated with mouse PD-1 targeting INTASYL mPH-762, in treating a subcutaneous Hepa1-6 model of murine hepatoma in C57BL/6N mice. Positive controls included JQ-1, a small molecule inhibitor of BRD4 and anti-mouse PD-1 monoclonal antibody (mAb) or both treatments.

"We are excited by these new in vivo study results presented at ASCO (Free ASCO Whitepaper) today, which highlight the potential of INTASYL as a mono- or dual-targeting therapy platform. By using doses that were well below the optimal single agent therapeutic dose identified in previous animal studies, we can obtain very high efficacy by dual-targeting BRD4 and PD-1. Even at these suboptimal concentrations, the dual-targeting INTASYL compound elicited complete responses in 83% of mice, and outperforming JQ-1 and anti-PD-1 mAb treatments, either used individually or in combination. Data from the study also suggests that the dual targeting INTASYL treatment resulted in a superior safety profile, as compared to the JQ-1 and anti-PD-1 mAb treatments," stated Dr. Simon Fricker, Phio’s VP of Research. He added, "These data further support our message that INTASYL can outperform other therapeutic approaches, and that synergistic drug combination approaches can be easily executed with a single INTASYL formulation."

A poster further detailing the data presented at the 2021 ASCO (Free ASCO Whitepaper) Annual Meeting titled "INTASYL self-delivering RNAi therapy specifically dual-targeting BRD4 and PD-1 elicits complete tumor responses and evidence of synergy in a subcutaneous Hepa1-6 model of murine hepatoma in C57BL/6N mice" will be made available on the "Investors – Events and Presentations" section of the Company’s website (click here).

On June 4, 2021 Pacylex Pharmaceuticals, an oncology company unlocking a new approach to cancer therapy, and Greenfire Bio, a new Life Science development and investment company, reported the closing of Series A financing for Pacylex (Press release, Greenfire, JUN 4, 2021, View Source [SID1234583545]). These funds will be used to support the initial Phase 1 clinical investigation of PCLX-001, a first-in-class N-myristoyltransferase (NMT) inhibitor, in Diffuse Large B-Cell Lymphoma and solid tumor patients. Pacylex is leading the development of novel therapies targeting the biological process of myristoylation in cancer.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We are excited to be a catalyst for this new innovation in oncology" said Ajit Gill, CEO of Greenfire Bio. "Our goal is to build a portfolio of potential breakthroughs in medicine, and we look forward to seeing PCLX-001 move into the clinic."

"The support from Greenfire Bio is essential for our transformation into a clinical stage company", said Michael Weickert, CEO of Pacylex. "Pioneering a new target and first-in-class therapy is extraordinarily important to expand cancer treatment options and improve patient outcomes. We are delighted to find the right investor with an appreciation for this groundbreaking work."
Clinical site preparations are underway for the open label, dose escalation, Phase 1 clinical trial, principally to evaluate the safety of PCLX-001. The study will enroll 20-30 patients and the Company anticipates that enrollment will begin within the next month. A No Objection Letter from Health Canada was received by Pacylex on March 8, 2021, authorizing the planned Phase 1 Trial of PCLX-001 in relapsed/refractory B-cell Non-Hodgkin Lymphoma and advanced solid malignancies. PCLX-001 is believed to be the first NMT inhibitor that will be clinically tested. Three principal investigators will oversee the clinical study at three clinical sites in Canada: Dr. John Kuruvilla at Princess Margaret Cancer Centre in Toronto, Dr. Randeep Sangha at the Cross Cancer Institute in Edmonton and Dr. Laurie Sehn at the British Columbia Cancer Center in Vancouver.

PCLX-001

PCLX-001 is a small molecule, first-in-class NMT inhibitor, originally developed by the University of Dundee Drug Discovery Unit as part of a program to treat African sleeping sickness funded by Wellcome Trust. Pacylex is developing PCLX-001, which has excellent oral bioavailability, to treat leukemia and lymphoma. PCLX-001 selectively kills cancer cells and completely regresses (eliminates) tumors in animal models of acute myeloid leukemia (AML), diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). PCLX-001 has also been shown to inhibit the growth of lung and breast cancer tumors in animal models. In leukemia, lymphoma and breast cancer patients, the level of NMT2 is correlated with survival, suggesting an important biological role in these cancers. In tests using cultured cancer cells in vitro, PCLX-001 is at least ten times as potent as ibrutinib (Imbruvica) and dasatinib (Sprycel), two clinically approved drugs currently used to treat hematologic malignancies.

On June 4, 2021 Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company, reported that presented interim results from the Phase II SUMMIT basket trial, assessing the efficacy of neratinib in patients with EGFR exon 18-mutant non-small cell lung cancer (NSCLC), including patients with central nervous system (CNS) involvement, at the virtual 2021 ASCO (Free ASCO Whitepaper) Annual Meeting (Press release, Puma Biotechnology, JUN 4, 2021, View Source [SID1234583593]). The presentation, entitled "Neratinib efficacy in a subgroup of patients with EGFR exon 18-mutant non-small cell lung cancer and central nervous system involvement: findings from the SUMMIT basket trial," is included in the Lung Cancer—Non-Small Cell Metastatic Poster Session (#9068).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The Phase II SUMMIT basket trial is an open-label, multicenter, multinational study that includes a cohort evaluating the safety and efficacy of neratinib administered daily to patients with EGFR exon 18-mutant non-small cell lung cancer (NSCLC). Patients received 240 mg of neratinib daily as a single agent with mandatory loperamide prophylaxis.

A cohort of 11 patients with EGFR exon 18-mutant NSCLC from the Phase II SUMMIT basket trial, including patients with central nervous system involvement, were evaluated for safety and efficacy. Prior lines of therapies included EGFR tyrosine kinase inhibitors (TKIs) (91%), chemotherapy (55%) and checkpoint inhibitors (IOs) (27%). Patients with stable, asymptomatic CNS metastasis were enrolled. Of the 11 patients, 3 patients had baseline CNS metastasis.

Of the 10 evaluable patients who had previously been treated with an EGFR tyrosine kinase inhibitor, 6 patients (60%) experienced a partial response (PR), and 4 patients (40%) demonstrated a confirmed partial response. Four additional patients showed stable disease (SD) lasting ≥16 weeks – bringing the experienced clinical benefit that includes confirmed complete response or partial response or stable disease for at least 16 weeks to 80%. The median duration of response (DOR) was 7.5 months, and the median progression-free survival (PFS) was 9.1 months with some patients remaining on treatment. Of the 3 patients who had CNS metastases, best responses were 2 PR and 1 SD and individual PFS times were 1.9 to 9.1 months. These results suggest that neratinib can be a potential treatment option for patients with NSCLC and hard-to-treat CNS metastases.

Neratinib was well tolerated in this study, with no occurrences of grade 3 diarrhea reported and there was no incident of any patient requiring a dose hold, dose reduction, hospitalization, or discontinuation of treatment due to diarrhea.

Jonathan W. Goldman, MD, Associate Professor of Hematology & Oncology, Associate Director of Drug Development and Director of Clinical Trials in Thoracic Oncology at UCLA, an investigator on the trial, said, "EGFR exon 18-mutant lung cancer patients have no effective targeted options after first-line FDA-approved EGFR TKI therapy. This study shows that neratinib has the potential to be an efficacious and safe option to treat their disease, possibly with CNS activity as well."

Alan H. Auerbach, Chief Executive Officer and President of Puma, added, "The descriptive findings from this study indicate that neratinib may have a role as a treatment option for rare cancers. We are excited to explore the full potential of neratinib and help patients with difficult to treat conditions."

On June 4, 2021 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported the presentation of new and updated data on giredestrant (formerly known as GDC-9545), an investigational next generation oral selective oestrogen receptor degrader (SERD), in people with hormone receptor (HR)-positive, HER2-negative breast cancer (Press release, Hoffmann-La Roche, JUN 4, 2021, View Source [SID1234583529]). Breast cancer is now the most common cancer in the world, with HR-positive being the most common subtype representing 70% of cases.1,2 Data from these studies will be presented at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, which will be held June 4-8, 2021.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We’re encouraged by the results of these ongoing giredestrant studies which form part of a comprehensive clinical development programme in HR-positive breast cancer," said Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development. "Prolonged treatment durations and risk of relapse can represent significant challenges for patients, therefore a need remains for more effective and tolerable treatment options."

The data from two phase I studies presented at ASCO (Free ASCO Whitepaper) show giredestrant’s promising clinical activity and safety profile in HR-positive, HER2-negative breast cancer:

NCT03916744: Interim analysis of this window of opportunity study in the post-menopausal, neoadjuvant (preoperative) setting showed giredestrant’s consistent and compelling activity.3

The pharmacodynamic effect of giredestrant was assessed using the Ki67 proliferation biomarker, which indicates the ability of a therapy to suppress tumour growth.
Giredestrant showed promising impact on tumour cell proliferation after ~14 days of treatment; a mean reduction of Ki67 of 78% (95% CI:72-83); 55% of tumours exhibited complete cell cycle arrest defined as Ki67 ≤2.7%.
The safety profile of giredestrant in the neoadjuvant setting was consistent with its mechanism of action and there were no discontinuations due to adverse events (AEs).

NCT03332797: Updated data from this phase I study in the locally advanced/metastatic breast cancer setting showed that giredestrant as a monotherapy was well-tolerated, and had promising clinical activity, irrespective of the type of prior therapy or the presence of ESR1 mutations (mutations in the ESR1 gene are important mechanisms of resistance to hormone therapy).4,5

At 30mg, a 20% overall response rate was seen in patients with measurable disease at baseline, and clinical benefit rates of 55% and 76% were observed in the overall and ESR1 mutant subgroups, respectively.
Giredestrant showed notable activity in the ESR1 mutant subgroup indicating that giredestrant overcomes ESR1 mutations.
Giredestrant was well-tolerated at all doses (10–250mg); there were no dose limiting toxicities with giredestrant monotherapy; AEs were generally low grade.
A standardised once-daily 30mg dose has been selected for the giredestrant development programme, both as a monotherapy and in combination studies.

We are currently enrolling patients into two phase II studies (CoopERA and AcelERA) evaluating giredestrant in neoadjuvant oestrogen receptor (ER)-positive early breast cancer, and previously treated locally advanced or metastatic breast cancer respectively, as well as one phase III study (PersevERA), evaluating giredestrant plus palbociclib against letrozole plus palbociclib in patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer.6,7,8

The mainstay of treatment is to block oestrogen, but the side effects of this have a very significant impact on quality of life and can greatly affect treatment adherence.9,10 With giredestrant, we are striving to provide a more tailored, more effective and less debilitating treatment for HR-positive breast cancer.

Giredestrant received U.S. Food and Drug Administration (FDA) Fast Track Designation (FTD) for ER-positive, HER2-negative, second and third-line metastatic breast cancer on 15 December 2020. A FTD is a process designed to facilitate the development, and expedite the review of drugs to treat serious conditions and fill an unmet medical need.11

About giredestrant
Giredestrant is a next generation investigational SERD, designed to fully block ER signalling with robust receptor occupancy. Oestrogen encourages HR-positive breast cancer cells to grow by attaching to the ER. Giredestrant works by blocking this receptor to prevent the action of oestrogen, and in the process causes the receptor to be degraded. This investigational medicine has also shown efficacy regardless of ESR1 mutation status (mutations in the ESR1 gene are important mechanisms of resistance to hormone therapy).5,9,12,13

Orally given, giredestrant delivers a strong clinical efficacy and safety profile and has shown superior pre-clinical potency over other SERDs in development.12,14 The oral administration of giredestrant has the potential to transform the treatment experience for patients, offering greater convenience and a less painful option compared to therapies administered via intramuscular injection.

Giredestrant has a comprehensive development programme across a broad range of settings and treatment combinations for patients with HR-positive, HER2-negative breast cancer. A standardised once-daily 30mg dose has been selected for the giredestrant development programme, both as a monotherapy and in combination studies.

About NCT0391674415
An open-label, short-term window study due to explore the safety, pharmacokinetics, pharmacodynamics, and activity of giredestrant in around 75 post-menopausal women with untreated stage I-III ER-positive/HER2-negative early breast cancer. The primary endpoint of the study will be the change in Ki67 scores (a measure of how quickly cancer cells are proliferating) between biopsies taken before and after treatment. Secondary endpoints include safety outcomes and plasma concentration of giredestrant.

About NCT0333279716
An ongoing phase Ia/b first-in-human, multi-centre, open-label, dose escalation, dose expansion study. The study is exploring the safety, pharmacokinetics, pharmacodynamics, and activity of giredestrant as a single agent, and in combination with palbociclib and/or luteinizing hormone-releasing hormone agonist, in 181 people with locally advanced or metastatic ER-positive/HER2-negative breast cancer. Primary endpoints of the study include the maximum tolerated dose of giredestrant and as well as safety outcomes. Secondary endpoints include plasma concentration levels of giredestrant and palbociclib over time, objective response rate, clinical benefit rate and duration of response.