On October 25, 2020 Dana-Farber Cancer Institute reported A novel agent that targets a mutated form of the KRAS gene – the most commonly altered oncogene in human cancers and one long considered "undruggable" – shrank tumors in most patients in a clinical trial with manageable side effects, researchers reported at the 32nd EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Therapeutic, which is taking place online (Press release, Dana-Farber Cancer Institute, OCT 25, 2020, View Source;bowel–and-other-solid-tumors/ [SID1234568953]).

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The KRYSTAL-1 (NCT03785249) phase I/II trial tested the agent, adagrasib (MRTX849), in patients with non-small lung cancer (NSCLC), colorectal cancer, and other solid tumors such as pancreatic, endometrial, and ovarian cancer. At today’s symposium, Pasi A. Jänne, MD, PhD, Director of the Lowe Center for Thoracic Oncology at Dana Farber Cancer Institute, reported that of 51 patients with NSCLC participating in the trial, 45% had an objective response, meaning their tumors shrank by 30% or more and did not grow or spread to other parts of the body. The disease control rate was 96%, meaning that 49 of the patients had a partial or complete response or stable disease.

Among the 14 patients in the phase I/Ib cohort who had been followed for a longer period of time (median time of 9.6 months), an objective response was seen in six (43%). Five of these six patients were still in ongoing treatment as of the cut-off date, with four of these six patients on the duration of treatment has lasted for more than 11 months.

Adagrasib targets a KRAS mutation called G12C, which is associated with a poor prognosis and lack of response to standard treatments. The mutation occurs in approximately 14% of lung adenocarcinomas, the most common subtype of NSCLC, 3-4% of colorectal cancers, and 2% of pancreatic cancers. This translates into well over 100,000 people each year worldwide.

Adagrasib works by irreversibly and selectively binding to KRAS G12C in its inactive state, blocking its ability to send cell-growth signals and leading to cancer cell death.

Until recently no KRAS inhibitor had moved beyond preclinical testing, but in 2018 adagrasib was among several KRAS inhibitors approved by the U.S. Food and Drug Administration (FDA) for study in clinical trials beginning in January 2019. All patients in the KRYSTAL-1 phase I/II trial had advanced cancer and had previously received standard treatment for their disease, including chemotherapy and immunotherapy.

As part of the trial, researchers analyzed the treatment-related adverse side effects in all 110 patients who participated in the phase I/Ib and II parts of the trial, including those with colorectal cancer and other solid tumors, as well as those with NSCLC. Side effects included nausea (54%), diarrhea (51%), vomiting (35%), fatigue (32%), and increased levels of an enzyme that indicates minor liver irritation (20%). The only serious adverse side effect to occur in more than one patient was low sodium in the blood, which occurred in two patients.

"KRAS G12C patients are a population for which there are no proven targeted therapies. Once chemotherapy or immune therapy fails in a patient, treatment options are limited," said Jänne. "The fact that we are seeing responses in 45% of patients with adagrasib is incredibly meaningful as it opens up the possibility of a new treatment option for this subset of lung cancer patients."

Results for 31 trial participants with colorectal cancer or other solid tumors were presented by Melissa L. Johnson, MD, associate director of the Lung Cancer Research Program and Drug Development at the Sarah Cannon Research Institute, Tennessee Oncology.

Of 18 patients with colorectal cancer who could be evaluated, three (17%) had a confirmed objective response and two of them continue to receive treatment. Disease control was seen in 17 of the patients (94%) and 12 of these patients continue to be treated, including ten of 18 patients on treatment for greater than four months.

Among the six patients with other solid tumors who could be evaluated, a partial response was confirmed in one patient each with endometrial cancer, pancreatic cancer, ovarian cancer, and cancer of the bile duct (cholangiocarcinoma). Two appendiceal cancer patients who were treated achieved stable disease. All six patients remain on the treatment.

Researchers are also looking at combining adagrasib with other targeted therapies, such as pembrolizumab for NSCLC, cetuximab for colon cancer, investigational SHP-2 inhibitor, TNO-155, in either NCSLC or colon cancer and afatinib for NSCLC.

This study was sponsored by Mirati Therapeutics, Inc. Jänne is a compensated scientific advisor for Mirati Therapeutics.

Abstract no: 3 LBA, "KRYSTAL-1: Activity and Safety of Adagrasib (MRTX849) in Advanced/Metastatic Non–Small-Cell Lung Cancer (NSCLC) Harboring KRAS G12C Mutation", by Pasi Jänne, presented in the Late Breaking and Best Proffered Papers Plenary session 2, channel 1, 15.45 hrs CET on Sunday 25 October:

View Source!abstractdetails/0000902150

Abstract no: 4 LBA, "KRYSTAL-1: Activity and Safety of Adagrasib (MRTX849) in Patients with Colorectal Cancer (CRC) and Other Solid Tumors Harboring a KRAS G12C Mutation", by Melissa Johnson, presented in the Targeting Oncogenic RAS signalling: New Approaches To An Old Problem scientific session, Channel 2, 19.30 hrs CET on Sunday 25 October: View Source!abstractdetails/0000902140

On October 24, 2020 ESSA Pharma Inc. (Nasdaq: EPIX) (TSXV: EPI), a clinical-stage pharmaceutical company focused on developing novel therapies for the treatment of prostate cancer, reported new preclinical data on ESSA’s clinical candidate, EPI-7386, at the 32nd EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Annual Symposium on Molecular Targets and Cancer Therapeutics ("ENA") (Press release, ESSA, OCT 24, 2020, View Source [SID1234568960]).

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In an oral poster presentation titled, "The pre-clinical characterization of the N-terminal domain androgen receptor inhibitor, EPI-7386, for the treatment of prostate cancer", was published on Saturday, October 24th.

The studies highlight new information about EPI-7386 including:

In an in vitro cellular thermal shift assay (CETSA), EPI-7386 was shown to physically interact with the both the full-length and the splice variant (AR-V7) form of the androgen receptor ("AR").
In an in vitro full-length AR-driven cellular model (LNCaP), RNAseq data was analyzed by pathway enrichment analysis. EPI-7386 demonstrates largely similar modulation of AR-regulated genes compared to enzalutamide, but with additional unique elements.
EPI-7386 exhibits superior activity to enzalutamide in the AR-V7-driven cellular models LNCaP95 and 22Rv1 by modulating AR-driven gene expression with or without the addition of an external androgen.
"Previously, we presented in vitro data demonstrating that EPI-7386 binds to the full-length androgen receptor and can inhibit the transcription of AR-regulated genes. These new data demonstrate that EPI-7386 can also physically interact with the splice variant form, AR-V7, of the androgen receptor and inhibit its activity. The importance of this interaction with AR-V7 is seen through the superior transcriptional inhibition of AR-regulated genes by EPI-7386 compared to enzalutamide in the AR-V7-driven cell models LNCaP95 and 22Rv1. Together, these data provide important new insights into mechanistic aspects related to the binding and utility of EPI-7386 against AR-V7 splice-variant driven prostate cancer models. The data further strengthen the rationale for studying EPI-7386 in men with prostate cancer resistant to current anti-androgens." said Dr. David R. Parkinson, President and Chief Executive Officer.

On October 24, 2020 Syros Pharmaceuticals (NASDAQ:SYRS), a leader in the development of medicines that control the expression of genes, reported initial safety, pharmacokinetics (PK) and pharmacodynamics (PD) data from the ongoing dose-escalation portion of its Phase 1 clinical trial of SY-5609 in patients with select solid tumors (Press release, Syros Pharmaceuticals, OCT 24, 2020, View Source [SID1234568959]). SY-5609 is a highly selective and potent oral cyclin-dependent kinase 7 (CDK7) inhibitor. These early data demonstrate proof of mechanism in patients with advanced solid tumors and establish a maximum tolerated dose (MTD) for continuous daily dosing. The data are being presented in a poster session at the 32nd EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium.

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"These early findings from our Phase 1 trial of SY-5609 reinforce our conviction in CDK7 inhibition as a potentially transformative targeted approach for difficult-to-treat cancers," said David A. Roth, M.D., Chief Medical Officer of Syros. "As we move forward in this trial, we are committed to fully exploring the potential of SY-5609. To that end, we opened the trial to pancreatic cancer patients, expanded a cohort to focus on lung cancer patients, and also expanded the combination cohort in treatment-resistant breast cancer patients. Additionally, we opened cohorts evaluating alternate dosing regimens, all with the goal of identifying optimal next steps for pursuing single-agent and combination development opportunities and ultimately delivering the greatest benefit to patients."

Early Data Demonstrate Proof-of-Mechanism at Tolerable Doses

Syros presented initial data from its ongoing Phase 1 multi-center, open-label, dose-escalation study of SY-5609 in patients with advanced breast, colorectal, lung, ovarian or pancreatic cancer, or other solid tumors with Rb pathway alterations. The study also includes a cohort evaluating SY-5609 in combination with fulvestrant in CDK4/6 inhibitor-resistant HR-positive breast cancer patients.

As of August 21, 17 patients had been enrolled in the trial and were eligible for safety, PK and PD analysis. Patients were either treated with continuous daily dosing of single-agent SY-5609 at 1, 3, 4 or 5 mg, or for three weeks on and one week off at 3 mg in combination with fulvestrant. The median age of the patients enrolled in the study was 64. Patients were heavily pretreated with a median of four prior therapies. The MTD for continuous daily dosing was achieved at 3 mg. The data showed that:

SY-5609 demonstrated dose-dependent increases in POLR2A mRNA expression, a PD marker being used in the trial to measure CDK7 biological activity.
Notably, increases in POLR2A in patients treated at 3 mg daily reached levels associated with tumor regressions in preclinical models, as well as with levels of CDK7 target engagement at which a clinical response and apoptosis were observed in a trial of patients treated with a first-generation IV CDK7 inhibitor.
SY-5609 demonstrated approximately dose-proportional PK as both a single agent and in combination, minimal accumulation with repeat dosing, and a steady state half-life compatible with once-daily dosing.
The majority of adverse events reported with SY-5609 as a single agent were low grade. The most common AEs were nausea, diarrhea, fatigue, platelet count decrease, and vomiting.
The safety profile of SY-5609 in combination with fulvestrant was consistent with that of single-agent SY-5609.
Five of the 13 patients treated with single-agent SY-5609 were response evaluable, and of those, three achieved stable disease and two had progressive disease; one of the four patients treated in the combination cohort was response evaluable and had progressive disease.
The Phase 1 trial continues to actively enroll patients with select solid tumors, including the recently expanded single-agent cohort in lung cancer patients and combination cohort in breast cancer patients, to further evaluate the 3 mg daily dose in focused patient populations. The trial has also been opened to patients with advanced pancreatic cancer, another tumor type that has demonstrated sensitivity to SY-5609 in preclinical models. Additional cohorts are evaluating alternate regimens, supported by preclinical data showing that intermittent regimens of SY-5609 induced tumor regressions.

Syros expects to report additional dose-escalation data, including clinical activity data, in mid-2021. Additional details about the Phase 1 trial of SY-5609 can be found using the identifier NCT04247126 at www.clinicaltrials.gov.

On October 24, 2020 Turning Point Therapeutics, Inc. (NASDAQ: TPTX), a precision oncology company developing next-generation therapies that target genetic drivers of cancer, reported initial clinical data from the ongoing Phase 1 dose finding portion of its SHIELD-1 study of drug candidate, TPX-0022, a potent inhibitor of MET and the associated cancer signaling pathways of SRC and CSF1R (Press release, Turning Point Therapeutics, OCT 24, 2020, View Source [SID1234568955]). The initial data highlighted preliminary clinical activity, including objective responses across multiple tumor types and a generally tolerable safety profile.

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The findings were reported in a late-breaking oral presentation by David Hong, M.D., Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center in the plenary session of the Molecular Targets and Cancer Therapeutics virtual symposium hosted by the European Organisation for Research and Treatment of Cancer (EORTC), the National Cancer Institute (NCI) and the American Association for Cancer Research (AACR) (Free AACR Whitepaper).

"Oncogenic alterations in MET – including exon 14 deletion, amplifications, fusions and activating kinase domain mutations – occur in many tumor types and patients continue to have limited available therapies," said Dr. Hong. "The initial data reported today for TPX-0022 is encouraging because it represents the potential for a new targeted therapy to improve the outcome in a wide range of MET-driven cancers."

TPX-0022, Phase 1 Initial Clinical Data
Twenty-two patients were treated across four dose levels from Sept. 2019 to the data cut-off date of Oct. 15, 2020. Patients included those with MET-altered non-small cell lung cancer (n=13), colorectal cancer (n=4), gastric or gastroesophageal (GE) junction cancer (n=4) and glioblastoma (n=1).

The median number of prior therapies was three (range 1 to 6), with all patients having received at least one prior line of chemotherapy and/or immunotherapy and the majority of patients having received multiple rounds of prior combination chemotherapy. Sixty-eight percent of patients had a baseline ECOG performance score of 1.

Preliminary efficacy data was available for 15 evaluable patients with baseline measurable disease and at least one post-baseline scan.

As of the 15 October 2020 data cut-off date:

Preliminary Safety and Pharmacokinetic (PK) Results (n=22)

A total of 22 patients with MET-dysregulated advanced solid tumors were treated with TPX-0022 at dose levels from 20 mg once daily (QD) to 120 mg QD.
TPX-0022 was generally well tolerated, with the most frequent treatment emergent adverse event (TEAE) being Grade 1 or 2 dizziness.
TEAEs reported in greater than 20 percent of patients were dizziness (55%); lipase increased (32%); fatigue (32%); amylase increased (27%); nausea (27%); vomiting (27%); constipation (23%); and anemia (23%).
The majority of treatment related adverse events (TRAEs) were Grade 1 or 2 and there were no Grade 4 or 5 TRAEs
The maximum tolerated dose had not been determined, with one dose-limiting toxicity of treatment-related Grade 2 dizziness at 120 mg QD.
PK data suggested sustained MET inhibition throughout the dosing interval across all doses.
Preliminary Efficacy Results (n=15)

A total of 15 patients were evaluable for efficacy by investigator assessment, including 10 who were MET TKI-naïve: four with colorectal cancer (CRC), three with non-small cell lung cancer (NSCLC), and three with gastric or GE junction cancer (GC or GEJ). In addition, five patients were MET TKI-pretreated, all with NSCLC.
Of 10 MET TKI-naïve patients, five achieved a partial response, including three with GC or GEJ cancer, one with CRC, and one with NSCLC. All three evaluable patients with gastric or GEJ tumors achieved a response.
Of the five responses, three patients achieved a confirmed response, and two patients remained on treatment in a response awaiting confirmation at the time of the data cut-off.
Of the five MET TKI-pretreated NSCLC patients, three patients treated with multiple rounds of prior therapy achieved a best response of stable disease with two patients showing tumor measurement improvements (-27%, and -75% accordingly).
Nine of 15 patients (9/15) achieved clinical benefit (confirmed and unconfirmed partial response or stable disease).
Six of 15 patients (6/15) remained on treatment with duration of treatment ranging from 7.6+ to 34+ weeks.
"We are encouraged by the emerging early safety and efficacy data across multiple tumor types, including the high unmet medical need area within MET-amplified gastric cancer where there are no approved targeted therapies," said Mohammad Hirmand, M.D., chief medical officer. "MET driven cancers affect a large and growing population of patients who have limited therapeutic options. Based on these early study findings, we look forward to advancing the development of TPX-0022."

The company anticipates initiating Phase 1 dose expansion after determining the recommended Phase 2 dose. Turning Point plans to discuss the ongoing Phase 1 SHIELD-1 study with the Food and Drug Administration (FDA) to potentially modify the trial into a registrational Phase 1/2 design. The company is targeting initiation of the Phase 2 portion in the second half of 2021, pending FDA feedback. In parallel, based on the SHIELD-1 study initial findings, a combination study with TPX-0022 and an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in patients with EGFR mutated MET-amplified NSCLC is also planned for initiation in the second half of 2021.

Repotrectinib Poster Presentations
In addition, preclinical data for the company’s lead drug candidate repotrectinib were reported in two poster presentations.

The first poster expanded on previous work presented in June at AACR (Free AACR Whitepaper) 2020 with additional preclinical data of repotrectinib in combination with the KRAS-G12C inhibitor, AMG-510, in a NSCLC xenograft tumor model. In preclinical studies, repotrectinib significantly enhanced efficacy of AMG-510 and showed a marked survival benefit in a KRAS G12C xenograft model when compared to AMG-510 alone.

Repotrectinib previously showed synergy in preclinical models with AMG-510 and inhibited KRAS G12C tumor cell proliferation, suppressed receptor tyrosine kinase upregulation induced by AMG-510, and reduced KRAS G12C tumor cell cytokine release. Similar results have since been obtained with other KRAS G12C inhibitors.

With the new results presented in a KRAS G12C xenograft tumor model, and previous data shown with repotrectinib in combination with a MEK inhibitor (presented at AACR (Free AACR Whitepaper) 2020), the company now plans to initiate a clinical combination study in KRAS mutant NSCLC in mid-2021. Further details on the design will be shared at the time of study initiation.

The second poster showed preclinical studies of repotrectinib as monotherapy and in combination with irinotecan and temozolomide in neuroblastoma cell lines and pediatric patient-derived xenograft (PDX) models. Repotrectinib combined with chemotherapy demonstrated increased anti-tumor activity compared to chemotherapy alone in an ALK-mutant neuroblastoma PDX model.

"With a growing body of supportive preclinical data, we are encouraged by the potentially broader role for repotrectinib across the treatment landscape," said Dr. Hirmand. "Repotrectinib’s inhibition of the cancer signaling pathways of SRC, FAK and JAK2, and its generally well-tolerated safety profile make it an ideal candidate for combination therapy. We look forward to advancing our combination strategy toward the initiation of clinical studies in 2021."

Webcast and Conference Call
Turning Point will host a webcast and conference call accompanied by a slide presentation to discuss the results from the SHIELD-1 Phase 1 study of TPX-0022 at 11:00 a.m. ET/8:00 a.m. PT today. Athena Countouriotis, M.D., president and chief executive officer, will host the call, which will also include Dr. Hirmand and Dr. Hong.

The discussion will be accessible through the "Investors" section of tptherapeutics.com or by dialing (877) 388-2118 (in the United States) or (470) 495-9489 (outside the U.S.) using conference ID 8655648. A replay will be available through the "Investors" section of www.tptherapeutics.com.

On October 24, 2020 Aileron Therapeutics (Nasdaq: ALRN) reported new positive clinical data from its ongoing Phase 1b trial demonstrating clinical proof of concept that treatment with ALRN-6924 prior to second-line topotecan administration resulted in a protective effect against severe anemia, thrombocytopenia and neutropenia in patients with p53-mutated small cell lung cancer (SCLC) (Press release, Aileron Therapeutics, OCT 24, 2020, View Source [SID1234568952]). The results are being featured today in a late-breaking poster presentation entitled, "Prevention of Chemotherapy-induced Myelosuppression in SCLC Patients Treated with Dual MDM2/MDMX Inhibitor ALRN-6924" (online here) at the 32nd EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Annual (ENA 2020) Symposium on Molecular Targets and Cancer Therapeutics.

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Chemotherapy, the backbone of treatment for millions of cancer patients, is unselective, meaning it cannot distinguish between cancer cells and healthy cells. As a result, chemotherapy destroys both cancer cells and rapidly dividing healthy cells, such as bone marrow cells, hair follicle cells and skin cells, among others. ALRN-6924 is the first and only chemoprotective therapy in clinical development that utilizes a biomarker strategy. Specifically, ALRN-6924 is a cell-permeating peptide drug designed to work intracellularly, activating wild-type p53 to selectively shield healthy cells from chemotherapy in patients who harbor p53-mutant tumors, approximately 50% of all cancer patients, without interrupting chemotherapy’s targeting of cancer cells.

"These proof-of-concept results for ALRN-6924 bring us a major step closer toward our goal of creating a new paradigm of proactive prevention of chemotherapy-induced side effects to address a significant unmet need among cancer patients," said Manuel Aivado, M.D., Ph.D., President and CEO of Aileron. "As a medical oncologist, I appreciate that physicians need assurance that a chemoprotective agent will not reduce the efficacy of chemotherapy or promote tumor growth. Designed to shield only healthy, non-p53-mutated cells and leave p53-mutated cancer cells fully vulnerable to chemotherapy, we believe ALRN-6924 provides that assurance. With ALRN-6924, we believe we have the potential to ultimately bring chemoprotection to patients across a broad set of cancer types, improving their quality of life and enhancing their anti-cancer response to chemotherapy."

Dr. Vojislav Vukovic, M.D., Ph.D., Chief Medical Officer at Aileron, commented, "We are extremely pleased to have achieved clinical proof of concept in our ongoing Phase 1b trial. ALRN-6924 has demonstrated the ability to protect very sick patients with SCLC against severe and life-threatening toxicities and side effects that are associated with a chemotherapy that is known to be highly toxic to the bone marrow. Importantly, we now have validation to expand clinical development into other types of p53-mutated cancers and chemotherapies and pursue our long-term vision to bring chemoprotection to all patients with p53-mutated cancers regardless of cancer type or chemotherapy."

Data Highlights

As of August 31, 2020, the data cut-off for this data presentation, a total of 26 adult patients were enrolled in the dose optimization part of the ALRN-6924 Phase 1b trial, evaluating treatment with ALRN-6924 given 24 hours prior to chemotherapy. 18 patients were enrolled across three ALRN-6924 dose levels (1.2 mg/kg, 0.6 mg/kg and 0.3 mg/kg) and an additional eight (8) patients were enrolled in a 0.3 mg/kg expansion cohort. 25 of these patients were evaluable per the trial protocol. ALRN-6924 was administered 24 hours before each dose of topotecan. Topotecan (1.5 mg/m2) was administered on days 1 through 5 of every 21-day treatment cycle. In the trial, toxicities were evaluated using the National Cancer Institute’s (NCI) Common Terminology Criteria for Adverse Events (CTCAE). Per the Phase 1b trial protocol, patients were not permitted to receive prophylactic G-CSF treatment in cycle 1.

Across all ALRN-6924 dose levels, Grade 3/4 anemia, Grade 3/4 thrombocytopenia and Grade 4 neutropenia (defined as <500/µL) were limited to 24%, 36% and 48% of patients, respectively. In the topotecan plus placebo arm of a recent third-party randomized Phase 2 trial in SCLC patients receiving topotecan (n=28), Grade 3/4 anemia, Grade 3/4 thrombocytopenia and Grade 4 neutropenia were reported in 63%, 70% and 76% of patients, respectively (Hart et al., ASCO (Free ASCO Whitepaper) 2019). In the ALRN-6924 trial, while chemoprotection effects were observed across all ALRN-6924 dose levels, the 0.3 mg/kg dose level showed the most robust chemoprotection results, with Grade 3/4 anemia, Grade 3/4 thrombocytopenia and Grade 4 neutropenia limited to 21%, 36% and 43% of patients, respectively. Additionally, none of the patients on ALRN-6924 experienced febrile neutropenia. In the topotecan plus placebo arm of the recent third-party randomized Phase 2 trial in SCLC patients receiving topotecan (n=29), febrile neutropenia was observed in 17% of patients (Hart et al., ASCO (Free ASCO Whitepaper) 2019). None of the patients treated at the 0.3 mg/kg ALRN-6924 dose level had hematological serious adverse events (SAEs) and only one patient (7%) received one red blood cell transfusion and one platelet transfusion1. In the topotecan plus placebo arm of the recent third-party randomized Phase 2 trial, 41% and 31% of SCLC patients received red blood cell and platelet transfusions, respectively (Hart et al., ASCO (Free ASCO Whitepaper) 2019). At the 0.3 mg/kg ALRN-6924 dose level, no patients required erythropoiesis-stimulating agents, and seven patients (50%) required G-CSF treatment.

_____________________
1 Finding followed EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium Late-Breaking Abstract submission.

ALRN-6924 (given 24h prior to chemotherapy) Phase 1b Trial
Bone Marrow-Related Key Toxicity Findings
Adverse Events (AEs)* NCI CTCAE ≥ Grade 3
Third Party
Randomized Phase 2
Trial in SCLC
Historical Control‡

Toxicity ALRN-6924
0.3 mg/kg +
Topotecan
N (%)
N=14 ALRN-6924
(All Dose Levels)
Topotecan
N (%)
N=25
Placebo
+ Topotecan
N (%)
N=28
All AEs 13 (93) 24 (96) 27 (96)
Anemia 3 (21) 6 (24) 17 (61)
Thrombocytopenia 5 (36) 9 (36) 16 (57)
Neutropenia 11 (79) 22 (88) 24 (86)
Febrile Neutropenia 0 0 5 (17) †

Neutropenia
Grade 4 6 (43)** 12 (48)** 21 (76)
*AEs based on laboratory values, as applicable
**For cycle 1 and for all treatment cycles
‡ Hart et al. ASCO (Free ASCO Whitepaper) 2019
† Febrile neutropenia reported for 29 patients

"Chemotherapy-induced toxicities historically have been viewed by the medical community as an unfortunate yet unavoidable reality associated with effective chemotherapeutics. With therapeutic advancements like ALRN-6924, I believe there is a potential to dramatically evolve that mindset," said Bojan Zaric, M.D., Ph.D., Head of Clinical Research, Head of Lung Cancer Clinic, Institute for Pulmonary Diseases of Vojvodina, Serbia, and Principal Investigator of the ALRN-6924 Phase 1b trial.

Dr. Zaric continued, "These Phase 1b data provide early yet important insights into ALRN-6924’s unique activity among chemoprotective agents in development, as well as potential advantages over the current standard of care therapies to address bone marrow toxicities. The findings suggest a strong potential for ALRN-6924 to protect patients undergoing chemotherapy against severe anemia, thrombocytopenia and neutropenia."

Enrollment in the dose optimization part of the Phase 1b trial (ALRN-6924 administered 24 hours before topotecan) is complete, and monitoring is ongoing with four of the evaluable patients continuing treatment past the data cut-off date.

Upcoming Milestones

Aileron continues to enroll patients in a schedule optimization part of the Phase 1b trial intended to determine whether ALRN-6924 given six hours prior to topotecan ("6h-schedule part") could be an alternative dosing schedule that could provide patients and healthcare providers with additional flexibility of when to administer ALRN-6924 before topotecan. The company expects to report final data from the Phase 1b trial, including data from the 6h-schedule part, in the first quarter of 2021.

In addition, in the fourth quarter of 2020, Aileron plans to initiate a clinical study of ALRN-6924 in healthy volunteers to characterize the time to onset, and the magnitude and duration of cell cycle arrest in human bone marrow relative to ALRN-6924 administration. Subject to the results of the healthy volunteer study and the final data from the Phase 1b trial, Aileron expects to initiate a non-small cell lung cancer program beginning with a Phase 1b trial in the fourth quarter of 2021 and a development program in a gastrointestinal cancer indication at a later point in time. Aileron does not currently plan to conduct additional development of ALRN-6924 in patients with SCLC.

"We designed a robust Phase 1b trial to enable us to evaluate multiple dose levels and schedules of ALRN-6924," said Dr. Vukovic. "We anticipate garnering additional insights from the alternative six-hour dosing schedule part of the Phase 1b SCLC trial and the healthy volunteer study that could provide a strong foundation for regulatory discussions around a registration program for ALRN-6924 in non-small cell lung cancer patients who are receiving platinum-based chemotherapy."

Conference Call and Webcast

Aileron will host a conference call and webcast on Monday, Oct. 26, 2020 at 8:30 a.m. ET to discuss the Phase 1b data and the company’s clinical development strategy to expand its chemoprotection research to multiple p53-mutated cancers and chemotherapies. To access the conference call, investors are invited to dial 877-705-6003 (domestic) or +1 201-493-6725 (international). The conference ID number is 13712133. A live audio webcast can be accessed by visiting the investor relations section of Aileron’s website at View Source The webcast will be archived on Aileron’s site for one year.

How ALRN-6924 Is Designed to Protect Healthy Cells from Chemotherapy

ALRN-6924 is being developed by Aileron as a novel chemoprotective medicine to selectively protect healthy cells in patients with cancers that harbor p53 mutations to reduce or eliminate chemotherapy-induced side effects.

Chemotherapy preferentially acts on cells that are cycling or undergoing the process of cell division. In cancer cells, the cell cycle is unchecked, which leads to uncontrolled cell proliferation, a hallmark of cancer. Certain types of healthy cells also naturally need to cycle, such as bone marrow cells, hair follicle cells, skin cells, and cells lining the oral cavity and the gastrointestinal tract. As a result, chemotherapy targets and kills both cycling healthy cells and cycling cancer cells. This, in turn, can lead to a spectrum of chemotherapy-induced side effects, from unpleasant to life-threatening and fatal.

ALRN-6924, an investigational first-in-class MDM2/MDMX dual inhibitor, is administered prior to chemotherapy to patients with p53-mutant cancers. ALRN-6924 is designed to activate normal p53 protein in patients’ healthy cells, temporarily and reversibly pausing cell cycling to selectively shield the patients’ healthy cells from chemotherapy. The protection is limited to healthy cells, as ALRN-6924 cannot work in p53-mutated cancer cells given that p53 has lost its function in those cells. Therefore, cancer cells continue to cycle uninterrupted and remain fully susceptible to destruction by
chemotherapy.