On May 29, 2020 RGENIX, Inc., a clinical stage biopharmaceutical company developing first-in-class small molecule and antibody cancer therapeutics, reported it is presenting data showing clinical activity in patients with advanced colorectal (CRC) tumors from a clinical trial of RGX-202, a first-in-class small molecule that inhibits a novel cancer metabolism pathway involved in supplying energy to cancer cells (Press release, Rgenix, MAY 29, 2020, View Source [SID1234558728]). RGENIX’s abstract, "Phase 1 trial of RGX-202, a first-in-class oral inhibitor of the SLC6a8/CKB pathway, in patients with advanced gastrointestinal (GI) solid tumors", is being presented by Dr. Johanna Bendell, Director of the Drug Development Unit at Sarah Cannon Research Center in Nashville, and clinical investigator and lead author on the study, as part of the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Scientific Program during an oral abstract session available on demand starting on May 29.

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RGX-202 is an oral small molecule inhibitor of the creatine transporter SLC6a8 that depletes intracellular phospho-creatine and ATP levels, leading to the death of cancer cells. The SLC6a8/CKB pathway was discovered using RGENIX’s proprietary miRNA-based target-discovery platform applied to KRAS mutant CRC. Due to increased metabolic demand, KRAS mutant tumors are highly susceptible to blockade of SLC6a8. In CKB-expressing (CKB+) pre-clinical models, RGX-202 treatment triggers tumor regressions across KRAS mutant subtypes. The ongoing Phase 1 trial of the compound is an escalation/expansion study of RGX-202 with or without FOLFIRI in patients with advanced GI tumors, and the trial will identify the maximum tolerated dose, or the dose at which multiple dose-limiting toxicities (DLTs) are not observed, and to determine the antitumor activity of the RGX-202.

As of April 29, 2020, 17 patients with advanced relapsed/refractory gastrointestinal cancers have been treated in 4 single agent dose escalation cohorts, with doses ranging from 600mg twice a day (BID) up to 3600mg BID. RGX-202 was well tolerated at all doses, with the majority (69%) of RGX-202-related adverse events (AEs) being grade 1 in severity with the most common AEs being nausea and vomiting. No DLTs were observed at any dose; notably, in the two highest cohorts, drug exposures predicted to be sufficient to inhibit human tumor growth from preclinical models were achieved along with concomitant pharmacodynamic effects.

10 patients were evaluable for response across all dose cohorts. Among the 5 evaluable patients with KRAS mutant CRC, 1 achieved a PR and 2 achieved stable disease, for an ORR of 20% and a disease control rate of 60%. Durable clinical benefit was observed in the highest dose cohort; a patient with KRAS G12V mutant CRC had a confirmed partial response of 40 weeks duration, and a patient with KRAS G13D mutant CRC experienced stable disease for 16 weeks. The ORR in all evaluable CRC patients – regardless of KRAS status – was 10% with a disease control rate (DCR) of 40%. A dose-escalation study assessing RGX-202 plus the chemotherapy regimen FOLFIRI is ongoing, with a planned expansion cohort in CKB+ CRC.

Masoud Tavazoie, MD, PhD, and Chief Executive Officer of RGENIX, said, "Though RGX-202 is still in an early stage of development, the results obtained to date are exciting. The single agent safety and activity profile provide a foundation for further development of RGX-202, including in combination regimens. Importantly, the results further validate our target discovery approach, which has now yielded two first-in-class clinical compounds, RGX-104 and RGX-202, both with single agent activity against novel targets discovered using our RNA-based platform technology. We look forward to sharing additional data from our programs as they progress through clinical development."

On May 29, 2020 Syros Pharmaceuticals (NASDAQ:SYRS), a leader in the development of medicines that control the expression of genes, reported new preclinical data for SY-5609, its highly selective and potent oral inhibitor of cyclin-dependent kinase 7 (CDK7) (Press release, Syros Pharmaceuticals, MAY 29, 2020, View Source [SID1234558727]). The data show that SY-5609 inhibits tumor growth, including inducing sustained regressions, at well-tolerated doses in colorectal cancer models, supporting the inclusion of colorectal cancer patients in Syros’ ongoing Phase 1 clinical trial. These data were presented as part of the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Scientific Program (ASCO20).

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"These data provide the first insights into the role of SY-5609 in driving anti-tumor activity in preclinical colorectal cancer models," said David A. Roth, M.D., Syros’ Chief Medical Officer. "Two hallmarks of colorectal cancer are increased expression of cancer-driving transcription factors and activating mutations in oncogenes that drive cell cycle progression. By inhibiting CDK7, SY-5609 attacks both of these processes. These new data add to the substantial body of scientific evidence that CDK7 inhibition is a potentially transformative targeted approach for difficult-to-treat cancers. We are actively enrolling patients, including those with colorectal cancer, in our Phase 1 trial and look forward to reporting initial dose-escalation data in the fourth quarter of 2020."

New Preclinical Data Highlight Therapeutic Potential of SY-5609 in Colorectal Cancer
Syros scientists conducted a series of preclinical studies of SY-5609 in colorectal cancer cell lines, as well as in 30 independent patient-derived xenograft (PDX) models of colorectal cancer, including BRAF-mutant, KRAS-mutant and wild-type models. The data show that SY-5609:

Potently inhibited proliferation and induced G2/M cell cycle arrest in KRAS- and BRAF-mutant colorectal cancer cell lines in vitro.
Induced dose-dependent tumor growth inhibition, including complete regressions that were sustained after treatment discontinuation, with repeated daily dosing at well-tolerated doses that were associated with dose-dependent expression changes in cell cycle markers E2F1 and CCNB1 and the transcriptional marker POLR2A in a BRAF-mutant PDX model.
Resulted in ≥ 50 percent tumor growth inhibition in 67 percent (20/30) of PDX models, and ≥ 90 percent tumor growth inhibition in 23 percent (7/30) of PDX models, including in models derived from heavily pre-treated patients, at well-tolerated doses.
Deeper responses, defined as ≥ 90 percent tumor growth inhibition, were observed more frequently in models with BRAF mutations (50 percent, 5/10) relative to KRAS-mutant or wild-type models (10 percent, 1/10 each).
Regressions were seen in two BRAF-mutant models and one KRAS-mutant model.
Design of the Ongoing Phase 1 Clinical Trial of SY-5609
In a separate presentation at ASCO (Free ASCO Whitepaper)20, Syros detailed the design of its ongoing Phase 1 trial of SY-5609. The multi-center, open-label, Phase 1 trial is expected to enroll approximately 60 patients with advanced breast, colorectal, lung or ovarian cancer, or solid tumors of any histology that harbor Rb pathway alterations. The primary objectives of the dose escalation are to assess safety and tolerability of escalating doses of SY-5609, with the goal of establishing a maximum tolerated dose (MTD). Additional objectives include assessments of anti-tumor activity, pharmacokinetics (PK), pharmacodynamics (PD), and potential predictive biomarkers.

The trial is designed to move efficiently through dose escalation, initiating with a single-patient accelerated titration design before transitioning to a more traditional 3+3 dose escalation. To further characterize safety, PK and PD, and explore early signals of clinical activity, any dose level that has cleared the dose-limiting toxicity evaluation may be expanded to enroll up to 12 patients while dose escalation proceeds. Additionally, an amendment is planned to assess the safety of escalating doses of SY-5609 in combination with fulvestrant in HR-positive/HER2-negative metastatic breast cancer patients who have progressed after treatment with a CDK4/6 inhibitor.

Syros expects to report initial safety, tolerability, PK and PD data from the dose escalation in the fourth quarter of 2020. Additional dose-escalation data, including clinical activity data, are expected in mid-2021.

The posters are now available on the Publications and Abstracts section of the Syros website at www.syros.com.

On May 29, 2020 mmunoGen, Inc. (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported initial data from the FORWARD II study evaluating mirvetuximab soravtansine in combination with Avastin (bevacizumab) in patients with medium and high folate receptor alpha (FRα)-expressing recurrent ovarian cancer for whom a non-platinum based combination regimen is appropriate (Press release, ImmunoGen, MAY 29, 2020, View Source [SID1234558726]). These findings were presented in an oral presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2020 Virtual Scientific Program.

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"The data presented at ASCO (Free ASCO Whitepaper) demonstrate the potential of mirvetuximab to serve as the combination agent of choice for both platinum-sensitive and platinum-resistant recurrent ovarian cancer," said Anna Berkenblit, MD, Senior Vice President and Chief Medical Officer of ImmunoGen. "We are particularly encouraged by the overall response rate of 64% observed in patients with high FRα expression, regardless of platinum status. We look forward to the continued evaluation of mirvetuximab with bevacizumab in this increasing population of recurrent ovarian cancer patients for whom a non-platinum based regimen would be appropriate.

"Despite the advances with PARP inhibitors and anti-angiogenic agents in newly diagnosed ovarian cancer, active, well-tolerated therapies for women with recurrent disease regardless of platinum status are still needed," said Lucy Gilbert, MD, Professor, and Director of the Gynecologic Oncology Division at McGill University Health Center in Montreal, Canada. "With this combination, the overall response rate in the platinum-resistant subset is more than twice the usual response rate for this population and similarly, in the platinum-sensitive subset, the overall response rate is higher than previously seen with platinum-based doublets. Given these responses and the favorable tolerability profile of this combination, these data are exciting and demonstrate the potential of mirvetuximab to address the growing unmet need in this patient population."

UPDATED DATA FROM FORWARD II DOUBLET COHORT WITH BEVACIZUMAB

Oral Presentation, Abstract 6004

The cohort enrolled 60 patients with a median age of 60 and a median number of 2 prior lines of therapy (range 1-4). Thirty-two patients (53%) had platinum-resistant disease with a platinum-free interval (PFI) of less than or equal to 6 months; 28 patients (47%) had platinum-sensitive disease – of which 20 patients (33%) had a PFI greater than 6 months and less than or equal to 12 months and 8 patients (13%) had a PFI greater than 12 months. The combination of mirvetuximab with bevacizumab in this cohort demonstrates promising anti-tumor activity with a favorable tolerability profile, particularly among patients with high levels of FRα expression, and is encouraging relative to outcomes with available therapies reported in similar populations. In today’s oral presentation, key updated data include:

In the overall patient population, objective responses were seen in 28 patients and the confirmed overall response rate (ORR) was 47% (95% CI, 34, 60).
In patients with high FRα expression (n=33), the confirmed ORR was 64% (95% CI, 45, 80), with an ORR of 59% (95% CI, 33, 82) in the platinum-resistant subgroup (n=17), and 69% (95% CI, 41, 89) in the platinum-sensitive subgroup (n=16).
With a median follow-up of 8.5 months and nearly half of patients with high FRα expression remaining on study, the duration of response and progression-free survival data are immature.
The adverse events (AEs) observed with the doublet were manageable and consistent with the side effect profiles of each agent. The most common treatment-related AEs were low-grade, including diarrhea, blurred vision, fatigue, and nausea; grade 3+ AEs were infrequent.
"Effective, tolerable treatment options for patients with recurrent ovarian cancer unfortunately remain limited," explained David O’Malley, MD, Professor, Division Director of Gynecology Oncology and Co-Director of the Gyn Onc Phase 1 Program, James Cancer Center and The Ohio State University Wexner Medical Center, and FORWARD II Principal Investigator. "These promising results confirm previously reported mirvetuximab plus bevacizumab data demonstrating a deeper and more durable tumor burden reduction in women whose tumors express high levels of FRα. These results add to the body of evidence that mirvetuximab can potentially be used to treat a broader patient population. I look forward to further evaluating these data as they mature."

Additional information can be found at www.asco.org.

ABOUT FORWARD II
FORWARD II is a Phase 1b/2 study of mirvetuximab in combination with Avastin (bevacizumab), carboplatin, or Keytruda (pembrolizumab) in patients with FRα-positive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancers, as well as a triplet combination of mirvetuximab plus carboplatin and bevacizumab in patients with FRα-positive platinum-sensitive ovarian cancer.

ABOUT MIRVETUXIMAB SORAVTANSINE
Mirvetuximab soravtansine (IMGN853) is an antibody-drug conjugate (ADC) comprising a folate receptor alpha (FRα)-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent to kill the targeted cancer cells.

On May 29, 2020 Alteogen Inc. (KOSDAQ:196170) reported at ASCO (Free ASCO Whitepaper) results from the First-in-Human (FIH), phase 1 study of ALT-P7, a HER2-targeting antibody-drug conjugate (ADC), in patients with HER2-positive advanced breast cancer (Press release, Alteogen, MAY 29, 2020, View Source [SID1234558725]).

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This is a FIH clinical trial of ALT-P7, a HER2-targeting ADC, and is a single-group, dose-escalation study designed to determine the maximum tolerated dose (MTD) and evaluate the safety of ALT-P7. For patients with HER2-positive breast cancer, the MTD of ALT-P7 was determined to be 4.5 mg/kg and was confirmed as the recommended dose for Phase II clinical trials (RP2D). Patients with HER2-positive breast cancer who participated in this clinical trial had received 6 types of systemic chemotherapy, including 4 types of HER2-targeted therapy. In this trial, a total of 27 patients received study drug. The most common grade 3/4 adverse event (AE) was neutropenia. Other common treatment-related AEs of any grade were myalgia, fatigue, sensory neuropathy, alopecia, pruritus, and neutropenia. The dose limit toxicities (DLTs) were observed at 4.8 mg/kg with a single case of febrile neutropenia, hyperbilirubinemia, myalgia, and hyponatremia. The disease control rate (DCR) of ALT-P7 was 72%, and the median progression-free survival (PFS) was 6.2 months (95% CI: 2.5-9.9 months).

"Compared with other ADC therapeutics which have microtubule-targeting payloads, ALT-P7 exhibited substantial tolerability," said Dr. Jae Hyeon Juhn, director of Regulatory Affair and Clinical Development of Alteogen. "The high tolerability together with a high disease control rate has the potential to offer a great benefit to patients, especially for those previously treated with several systemic & target therapeutics."

Based on the RP2D determined in this trial, Alteogen plans to evaluate the efficacy of ALT-P7 with RP2D in Phase 2 and also will evaluate its applicability for other HER2-positive carcinomas such as urethral epithelial cell cancer, or biliary tract cancer as well.

On May 29, 2020 Immune-Onc Therapeutics, Inc. ("Immune-Onc"), a clinical-stage cancer immunotherapy company, reported that the U.S. Food and Drug Administration (FDA) has cleared the company’s Investigational New Drug (IND) application for IO-202, an antibody targeting an immune inhibitory receptor LILRB4 (Press release, Immune-Onc Therapeutics, MAY 29, 2020, View Source [SID1234558724]). IO-202 is the first T-cell activator for acute myeloid leukemia (AML). In preclinical studies, IO-202 has shown evidence of activating T cell cytotoxicity against leukemia cells and blocking tumor infiltration. Immune-Onc’s first Phase 1 trial with IO-202 will evaluate its safety, tolerability, pharmacokinetics, pharmacodynamics and clinical activity in AML patients with monocytic differentiation and in chronic myelomonocytic leukemia (CMML) patients.

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"The FDA clearance to proceed with the first-in-human trial of IO-202 in AML and CMML is an important milestone for our company," said Charlene Liao, Ph.D., chief executive officer of Immune-Onc. "Acute myeloid leukemia is a devastating disease that needs new approaches and better treatment options. We look forward to working with investigators as we advance the first anti-LILRB4 antibody into the clinic."

The Phase 1 trial will begin with a dose-escalation phase to identify the optimal dose of IO-202. Once the recommended dose of IO-202 is selected, the trial will enroll patients in an expansion cohort to evaluate IO-202 as monotherapy. There is potential to evaluate IO-202 in combination with other agents with a protocol amendment. Biomarkers will be assessed to enable a mechanistic understanding of clinical data and inform future trials.

ABOUT AML and CMML

AML, the most common acute leukemia (blood and bone marrow cancer) in adults, is characterized by the proliferation of abnormal myeloblasts (a type of white blood cell) in the bone marrow. Nearly 20,000 new cases are expected in the U.S. in 2020. Despite advances in treatment, less than 30 percent of acute myeloid leukemia patients are alive five years after initial diagnosis.

CMML is a cancer that starts in blood-forming cells in the bone marrow and invades the blood. The condition is rare, with about 1,100 cases in the U.S. each year.

ABOUT IO-202

IO-202 is a first-in-class monoclonal antibody that blocks signaling of leukocyte immunoglobulin-like receptor B4 (LILRB4), an immune inhibitory receptor, with high binding affinity and specificity. In October 2018, Immune-Onc and The University of Texas announced the publication of pioneering research in Nature (DOI: 10.1038/s41586-018-0615-z) illuminating the roles of LILRB4 in immune suppression and tumor infiltration in AML. IO-202 is the first T-cell activator for AML. Preclinical studies showed that IO-202 can convert a "don’t kill me" to "kill me" signal by activating T cell killing of AML cells and a "don’t find me" to "find me" signal by inhibiting leukemia infiltration. IO-202 will be evaluated in AML and CMML in a Phase 1 trial, and Immune-Onc plans to explore its potential in other hematologic malignancies and solid tumors in future trials.