On November 16, 2018 VBL Therapeutics (Nasdaq: VBLT), is reported its results today from its Phase 3 GLOBE study in patients with recurrent glioblastoma (rGBM) which was designed to evaluate VB-111 in combination with bevacizumab (Avastin) (`treatment arm`), compared to bevacizumab (`control arm`) (Press release, VBL Therapeutics, NOV 16, 2018, View Source [SID1234531393]). In March 2018, VBL announced top-line data for the study, which did not demonstrate a benefit in overall survival (OS) or progression-free survival for the treatment arm relative to the bevacizumab control.

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The GLOBE data are being presented today at the 2018 Society for Neuro-Oncology Annual Meeting by Dr. Timothy Cloughesy, MD, Professor of Clinical Neurology and Director of the Neuro-Oncology Program, UCLA School of Medicine and principal investigator of the GLOBE trial. The data include further analyses of the GLOBE data including baseline prognostic factors and subgroups analysis. Data show that the baseline tumor volume, which is a significant prognostic factor in rGBM, was higher in the treatment arm compared to the control arm. Overall, the subjects in the study had relatively high tumor volume, as large-volume tumors were not an exclusion criterion. It is of interest that patients with smaller tumors (<15 cm3) appeared to respond better to the treatment arm, with numerically higher response rate and overall survival observed. Furthermore, a trend towards greater survival was observed in patients treated with VB-111 who reported fever. VB-111 was well tolerated, with a similar early termination rate in both the treatment and control arms. Most frequent adverse event was self-limited fever, starting several hours post therapy and usually resolving by 24 hours. As expected, a higher rate of SAEs and grade >=3 AEs was reported in the combination treatment arm.

Subsequent analyses have focused on the potential reasons for the major differences in outcomes between the positive VB-111 Phase 2 clinical trial in rGBM and the unsuccessful GLOBE results. The Phase 2 trial of VB-111 met the primary endpoint of OS benefit with median OS (mOS) of 13.6 months upon treatment with VB-111 as a single drug (`priming`) followed by adding bevacizumab to VB-111 upon further progression, compared to mOS of 6.8 months for the treatment arm in GLOBE (co-administration of VB-111 and bevacizumab, without any VB-111 monotherapy `priming` period).

Thorough analyses of the baseline risk factors of the Phase 2 and the Phase 3 treatment groups did not reveal any differences. Therefore, patient selection or different patient populations could not explain the difference between the results of the two studies. The only significant change between the Phase 2 and Phase 3 treatment cohorts was in the treatment regimen – the regimen for Phase 2 trial included priming with VB-111 whereas the regimen for GLOBE trial did not.

To test the hypothesis that concomitant treatment with bevacizumab may have a negative effect on VB-111 activity, the Company investigated this combination in a pre-clinical tumor model. The results indicate that treatment with VB-111 in combination with bevacizumab appears to block the anti-tumor the effect of VB-111, compared to VB-111 monotherapy. In addition, a retrospective analysis of a small cohort of 10 patients who were treated concomitantly with VB-111 and bevacizumab for safety evaluation (no priming), was inferior to what was observed with VB-111 priming in the Phase 2 study.

To better understand these results, the Company is collaborating with UCLA scientists in performing thorough analyses of MRI scans for VB-111-primed combination arm patients from the Phase 2 trial, compared to the un-primed combination arm patients in the GLOBE trial.

"Our initial exploratory analyses demonstrate clear radiologic responses over time in rGBM patients treated with VB-111 in the Phase 2 trial, both on VB-111 monotherapy and in combination with bevacizumab after priming with VB-111 alone, which were translated to overall survival. We are currently analyzing the GLOBE MRI scans to see if this signature of VB-111 activity is lost in the GLOBE combination group and will report the outcome upon completion of the analysis," said Dr. Cloughesy.

"The new analyses we have been conducting provide insight into how the VB-111 treatment regimen may influence its anti-tumor effect and help us understand why the positive Phase 2 data were not replicated in the GLOBE Phase 3 study," said Dror Harats, M.D., Chief Executive Officer of VBL Therapeutics. "We believe that priming with VB-111 without bevacizumab may be critical for the immune and vascular-disruptive/anti-angiogenic mechanism of VB-111 in rGBM. We continue to have confidence in the ongoing OVAL Phase 3 study of VB-111 in platinum-resistant ovarian cancer patients, whose protocol takes into account lessons learned from our GBM trial. The OVAL Phase 3 study is evaluating VB-111 in combination with chemotherapy rather than Avastin. The combination of VB-111 with paclitaxel worked well both in pre-clinical settings and in our Phase 2 for ovarian cancer, including in patients whose tumors progressed on prior treatment with Avastin. In OVAL, we are repeating exactly the same successful Phase 2 regimen."

For a link to the GLOBE presentation at SNO see: LINK

About the GLOBE study

The GLOBE pivotal Phase 3 trial was a randomized, controlled, double-arm, open-label study of VB-111 dosed every two months in combination with bevacizumab dosed every two weeks, compared to bevacizumab monotherapy. Key inclusion criteria included first or second progression of glioblastoma following standard of care treatment with temozolomide and radiation, a histologically confirmed diagnosis of glioblastoma and measurable disease by RANO criteria at progression.

The study was conducted under a Special Protocol Assessment (SPA) granted by the FDA, with full endorsement by the Canadian Brain Tumor Consortium (CBTC). VB-111 has received orphan drug designation in the United States and Europe and was granted Fast Track designation by the FDA for promising and meaningful long-term survival in patients with glioblastoma that has recurred following treatment with standard chemotherapy and radiation.

About Ofranergene Obadenovec (VB-111)

VB-111, a potential first-in-class anticancer therapeutic candidate, is the Company’s lead oncology product currently being studied in a Phase 3 trial for ovarian cancer. VB-111 has received orphan drug designation in both the US and Europe, and fast track designation in the US for prolongation of survival in patients with rGBM. In addition, VB-111 successfully demonstrated proof-of-concept and survival benefit in Phase 2 clinical trials in radioiodine-refractory thyroid cancer and recurrent platinum-resistant ovarian cancer. VB-111 has received an Orphan Designation for the treatment of ovarian cancer by the European Medicines Agency (EMA).

On November 16, 2018 Stemline Therapeutics, Inc. (Nasdaq: STML), a biopharmaceutical company focused on the development and potential commercialization of novel oncology therapeutics, reported that data from the Phase 2 trial of SL-701 in patients with second-line glioblastoma (GBM) were selected for oral presentation at the 23rd Annual Meeting of the Society of Neuro-Oncology (SNO) being held November 15-18, 2018 in New Orleans, LA (Press release, Stemline Therapeutics, NOV 16, 2018, View Source [SID1234531394]).

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Details on the presentation are as follows:

Title: Phase 2 trial of SL-701 + bevacizumab in patients with previously treated glioblastoma (GBM) meets primary endpoint of OS-12, with preliminary correlation between long-term survival and target-specific CD8+ T cell immune response
Presenter: David Peereboom, MD; Cleveland Clinic
Abstract: ATIM-06
Date/Time: Friday, November 16, 2018 – 4:25 PM CT

A copy of the oral presentation will be available on the Stemline website (www.stemline.com), under the Scientific Presentations tab, following the SNO presentation.

On November 16, 2018 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported its updated data from the ongoing Phase 1 study evaluating single agent AG-881 in advanced glioma (Press release, Agios Pharmaceuticals, NOV 16, 2018, View Source [SID1234531460]). The data were featured in an oral presentation at the Society for Neuro-Oncology (SNO) Annual Meeting in New Orleans. AG-881 is an investigational, oral, selective, potent inhibitor of the mutant isocitrate dehydrogenase-1 (IDH1) and IDH2 enzymes and was designed for enhanced brain penetrance for development in IDH-mutant glioma.

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"With additional follow-up, the AG-881 Phase 1 dose-escalation data continue to show a favorable safety profile at the doses selected for the perioperative study. Longer treatment duration and a reduction in tumor growth rates are encouraging signs of clinical activity in low-grade glioma," said Ingo Mellinghoff, M.D., Memorial Sloan Kettering Cancer Center, an investigator for the study. "Ultimately, use of an IDH inhibitor in this difficult-to-treat disease has the potential to improve the current treatment paradigm by delaying the multiple rounds of surgery, radiation and chemotherapy that many patients endure."

"With no curative or approved targeted therapies and a high frequency of IDH1 mutations in low-grade glioma, we are committed to advancing one of our IDH inhibitors to a registrational study in this disease," said Chris Bowden, M.D., chief medical officer at Agios. "We are continuing to collect clinical data for both ivosidenib and AG-881, along with feedback from regulators and the neuro-oncology community, to make an internal decision on our glioma pivotal strategy by the end of this year."

Study Status

AG-881 is being evaluated as a single agent in an ongoing Phase 1 dose-escalation trial in IDH1/2 mutant advanced solid tumors, including glioma. Enrollment was completed in June 2017. Dose escalation data as of March 29, 2018 were presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. As of the updated July 20, 2018 data cut-off, study design, enrollment and baseline characteristics of the 52 glioma patients remain unchanged, as reported below.

Forty-eight percent of patients (n=25) had World Health Organization (WHO) classified Grade 2 tumors, 42% (n=22) had Grade 3 tumors, 8% (n=4) had Grade 4 tumors and 2% (n=1) was unknown.
The median age of these patients is 42.5 years (ranging from 16-73 years).
Patients received a median of two prior systemic therapies (ranging from one to six).
Seventy-three percent of patients (n=38) had previously received temozolomide and 58% percent (n=30) had previously received radiotherapy.
Patients received daily doses of AG-881 ranging from 10 mg to 300 mg.
Updated safety and efficacy data on the 52 patients with enhancing and non-enhancing glioma, including an exploratory tumor volume growth rate analysis, are reported below.

Fourteen patients remain on treatment, including 13 patients with non-enhancing disease.
Of the 38 patients who discontinued treatment, 76.3% (n=29) discontinued for disease progression and 5.2% (n=2) discontinued due to an AE.
The median treatment duration was 6.3 months (ranging from 0.2-32 months) for all glioma patients, 15 months (ranging from 1-32 months) for non-enhancing glioma and 3.25 months (ranging from 0.2- 32 months) for patients with enhancing disease.
Thirty-seven percent of patients (n=19, including 15 patients with non-enhancing disease) remained on treatment for ≥1 year.
Safety Data

The safety analysis conducted for all 52 glioma patients as of the data cut-off demonstrated that AG-881 continues to have a favorable safety profile at dose levels below 100 mg.

The majority of adverse events (AEs) reported by investigators were mild to moderate, with the most common (>30%) being increases in alanine aminotransferase (ALT) (n=23), increases in aspartate aminotransferase (AST) (n=21), headache (n=19) and fatigue (n=17).
Grade 3 or higher AEs were observed in 19% of all patients (n=10). AEs occurring in more than one patient included seizure (n=4), ALT increases (n=3) and AST increases (n=2).
As reported in June, dose limiting toxicities (DLTs) of Grade 2 or higher elevated transaminases occurred in five glioma patients at the higher dose levels (≥100 mg) and resolved to Grade ≤1 with dose modification or discontinuation. There were no new DLTs reported as of the new data cut-off or any treatment-related on-treatment deaths.
Doses of 10 mg and 50 mg are under evaluation in an ongoing perioperative study in non-enhancing glioma.
Efficacy Data

Efficacy data from the 52 glioma patients (22 with non-enhancing and 30 with enhancing disease) as of the data cut-off showed:

One patient with non-enhancing disease and a 1p19q co-deletion had a confirmed / sustained partial response according to the investigator by Response Assessment in Neuro-Oncology for low grade glioma (RANO-LGG) and remains on treatment.
One patient with non-enhancing disease and a 1p19q co-deletion had a confirmed / sustained minor response according to the investigator by RANO-LGG and remains on treatment.
Sixty-nine percent of patients (n=36) had a best response of stable disease, including 82% (n=18) patients with non-enhancing disease.
For non-enhancing patients with available data (n=18), the average volumetric six-month tumor growth was 6.8% following treatment with AG-881; pre-treatment volumetric growth rates were not available for these patients. For a similar population of IDHm low-grade glioma patients in the ongoing Natural History study, the average six-month volumetric growth prior to treatment was 24.5%.
Ongoing Glioma Perioperative Study Presented in Trials in Progress Poster
A perioperative ‘window’ trial with ivosidenib and AG-881 (10 mg and 50 mg) in up to 45 IDH1m non-enhancing low-grade glioma patients is ongoing and being presented today as part of a trials in progress poster. The goal of the trial is to confirm CNS penetrance and tumor 2-HG suppression of ivosidenib and AG-881 as part of the strategy to finalize internal pivotal development plans by year-end 2018.

About Glioma
Glioma presents in varying degrees of tumor aggressiveness, ranging from slower growing (low-grade glioma) to rapidly progressing (high-grade glioma-Glioblastoma Multiforme). Common symptoms include seizures, memory disturbance, sensory impairment and neurologic deficits. The long-term prognosis is poor with a five-year survival rate of 33 percent. Approximately 11,000 low-grade glioma patients are diagnosed annually in the U.S. and EU and approximately 80 percent have an IDH1 mutation.

On November 15, 2018 Exelixis, Inc. (Nasdaq: EXEL) reported that its partner Ipsen received approval from the European Commission (EC) for CABOMETYX (cabozantinib) tablets as a monotherapy for hepatocellular carcinoma (HCC) in adults who have previously been treated with sorafenib (Press release, Exelixis, NOV 15, 2018, View Source;p=irol-newsArticle&ID=2377258 [SID1234531351]). This approval allows for the marketing of CABOMETYX in this indication in all 28 member states of the European Union, Norway and Iceland.

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"The approval of CABOMETYX in the Europe Union is a very important milestone for our partner Ipsen and marks significant progress for people living with liver cancer, which is the second-leading cause of cancer death worldwide," said Michael M. Morrissey, Ph.D., President and Chief Executive Officer of Exelixis. "This patient community is in dire need of new options to treat this aggressive disease, and we are excited to work with Ipsen to make this treatment available to patients in the European Union and other countries worldwide."

Under the terms of the Collaboration Agreement with Ipsen, Exelixis will receive a milestone payment of $40 million for the approval of the second-line treatment of HCC. This milestone will be paid by Ipsen within the next 70 days.

"Today’s European Commission approval of CABOMETYX provides a much-needed new option for HCC patients. Until now, physicians in Europe had only one approved therapy for the second-line treatment of this aggressive and difficult-to-treat cancer. We are proud to offer CABOMETYX as an innovative treatment that has been shown to extend survival in previously treated patients with HCC," said Harout Semerjian, Chief Commercial Officer of Ipsen. "This new indication reinforces Ipsen’s commitment to improving patients’ lives through the expansion of the clinical benefit of CABOMETYX in the treatment of solid tumors."

The EC approval is based on results from the CELESTIAL trial of CABOMETYX in patients with advanced HCC who received prior sorafenib. In this phase 3 pivotal trial, CABOMETYX demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) versus placebo. CABOMETYX is also approved in the European Union for the treatment of advanced renal cell carcinoma (RCC) in adults who have received prior VEGF-targeted therapy and for previously untreated intermediate- or poor-risk advanced RCC.

On May 29, 2018, Exelixis announced that the U.S. Food and Drug Administration (FDA) accepted for filing the supplemental New Drug Application (sNDA) for CABOMETYX for previously treated advanced HCC and assigned a Prescription Drug User Fee Act action date of January 14, 2019. An sNDA is an application to the FDA that, if approved, will allow a drug sponsor to make changes to a previously approved product label, including modifications to the indication.

About the CELESTIAL Study

CELESTIAL is a randomized, double-blind, placebo-controlled study of cabozantinib in patients with advanced HCC conducted at more than 100 sites globally in 19 countries. The trial was designed to enroll 760 patients with advanced HCC who received prior sorafenib and may have received up to two prior systemic cancer therapies for HCC and had adequate liver function. Enrollment of the trial was completed in September 2017. Patients were randomized 2:1 to receive 60 mg of cabozantinib once daily or placebo and were stratified based on etiology of the disease (hepatitis C, hepatitis B or other), geographic region (Asia versus other regions) and presence of extrahepatic spread and/or macrovascular invasion (yes or no). No cross-over was allowed between the study arms during the blinded treatment phase of the trial. The primary endpoint for the trial is OS, and secondary endpoints include objective response rate and PFS. Exploratory endpoints include patient-reported outcomes, biomarkers and safety.

In October 2017, Exelixis announced that the independent data monitoring committee for the CELESTIAL study recommended that the trial be stopped for efficacy following review at the second planned interim analysis, with cabozantinib providing a statistically significant and clinically meaningful improvement in OS compared with placebo in patients with previously treated advanced HCC. The data, originally presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s Gastrointestinal Cancers Symposium (ASCO-GI) in January 2018, were published in The New England Journal of Medicine in July 2018.1

About HCC

Liver cancer is the second-leading cause of cancer death worldwide, accounting for more than 700,000 deaths and 800,000 new cases each year.2 In the U.S., the incidence of liver cancer has more than tripled since 1980.3 HCC is the most common form of liver cancer, making up about three-fourths of the estimated nearly 42,000 new cases in the U.S. in 2018.3 HCC is the fastest-rising cause of cancer-related death in U.S.4 Without treatment, patients with advanced HCC usually survive less than 6 months.5

About the Exelixis and Ipsen Collaboration

In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States and Japan. Under the terms of the Collaboration Agreement with Ipsen, Exelixis is entitled to receive a tiered royalty of 22 percent to 26 percent of annual net sales.

About CABOMETYX (cabozantinib)

CABOMETYX tablets are approved in the United States for the treatment of patients with advanced RCC. CABOMETYX tablets are also approved in: the European Union, Norway, Iceland, Australia, Switzerland, South Korea, Canada, Brazil and Taiwan for the treatment of advanced RCC in adults who have received prior VEGF-targeted therapy; in the European Union for previously untreated intermediate- or poor-risk advanced RCC; in Canada for adult patients with advanced RCC who have received prior VEGF targeted therapy; and in the European Union, Norway and Iceland for HCC in adults who have previously been treated with sorafenib. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan.

Please see Important Safety Information below and full U.S. prescribing information at View Source

U.S. Important Safety Information

Hemorrhage: Severe and fatal hemorrhages have occurred with CABOMETYX. In two RCC studies, the incidence of Grade ≥ 3 hemorrhagic events was 3% in CABOMETYX-treated patients. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage.
Gastrointestinal (GI) Perforations and Fistulas: In RCC studies, fistulas were reported in 1% of CABOMETYX-treated patients. Fatal perforations occurred in patients treated with CABOMETYX. In RCC studies, gastrointestinal (GI) perforations were reported in 1% of CABOMETYX-treated patients. Monitor patients for symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a fistula which cannot be appropriately managed or a GI perforation.
Thrombotic Events: CABOMETYX treatment results in an increased incidence of thrombotic events. In RCC studies, venous thromboembolism occurred in 9% (including 5% pulmonary embolism) and arterial thromboembolism occurred in 1% of CABOMETYX-treated patients. Fatal thrombotic events occurred in the cabozantinib clinical program. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or any other arterial thromboembolic complication.
Hypertension and Hypertensive Crisis: CABOMETYX treatment results in an increased incidence of treatment-emergent hypertension, including hypertensive crisis. In RCC studies, hypertension was reported in 44% (18% Grade ≥ 3) of CABOMETYX-treated patients. Monitor blood pressure prior to initiation and regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy. Discontinue CABOMETYX if there is evidence of hypertensive crisis or severe hypertension despite optimal medical management.
Diarrhea: In RCC studies, diarrhea occurred in 74% of patients treated with CABOMETYX. Grade 3 diarrhea occurred in 11% of patients treated with CABOMETYX. Withhold CABOMETYX in patients who develop intolerable Grade 2 diarrhea or Grade 3-4 diarrhea that cannot be managed with standard antidiarrheal treatments until improvement to Grade 1; resume CABOMETYX at a reduced dose.
Palmar-Plantar Erythrodysesthesia (PPE): In RCC studies, palmar-plantar erythrodysesthesia (PPE) occurred in 42% of patients treated with CABOMETYX. Grade 3 PPE occurred in 8% of patients treated with CABOMETYX. Withhold CABOMETYX in patients who develop intolerable Grade 2 PPE or Grade 3 PPE until improvement to Grade 1; resume CABOMETYX at a reduced dose.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in the cabozantinib clinical program. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.
Embryo-fetal Toxicity may be associated with CABOMETYX. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during CABOMETYX treatment and for 4 months after the last dose.
Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, nausea, decreased appetite, hypertension, PPE, weight decreased, vomiting, dysgeusia, and stomatitis.
Strong CYP3A4 Inhibitors: If concomitant use with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage.
Strong CYP3A4 Inducers: If concomitant use with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage.
Lactation: Advise women not to breastfeed while taking CABOMETYX and for 4 months after the final dose.
Hepatic Impairment: In patients with mild to moderate hepatic impairment, reduce the CABOMETYX dosage. CABOMETYX is not recommended for use in patients with severe hepatic impairment

On November 15, 2018 Syros Pharmaceuticals (NASDAQ: SYRS), a leader in the development of medicines that control the expression of genes, reported that data from the dose escalation portion of its Phase 1 trial of SY-1365, its first-in-class selective cyclin-dependent kinase 7 (CDK7) inhibitor, demonstrated proof-of-mechanism at tolerable doses in patients with advanced solid tumors (Press release, Syros Pharmaceuticals, NOV 15, 2018, View Source [SID1234531367]). These data, the first clinical data reported on a selective CDK7 inhibitor, were highlighted in an oral plenary session at the 30th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Molecular Targets and Cancer Therapeutics Symposium in Dublin.

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"These initial data on SY-1365 are highly encouraging," said Dejan Juric, M.D., Director of the Termeer Center for Targeted Therapies at Massachusetts General Hospital and a clinical investigator in the Phase 1 study of SY-1365. "Patient data from the SY-1365 dose escalation study confirm the unique mechanism-of-action of this agent and demonstrate an acceptable tolerability profile along with early signs of single-agent activity. These data, coupled with preclinical evidence showing robust anti-tumor activity in a range of relapsed and treatment-refractory cancer models, support the ongoing development of SY-1365 for patients who currently have few, if any, effective treatment options."

"As the first clinical data ever reported on a selective CDK7 inhibitor, these results mark an important milestone for SY-1365 and for the field of CDK7 inhibition," said David A. Roth, M.D., Syros’ Chief Medical Officer. "We believe CDK7 inhibition is a potentially transformative new approach for treating many cancers that have eluded effective treatment with existing approaches. Now that we have demonstrated proof-of-mechanism at tolerable doses, we are committed to thoroughly exploring the potential of CDK7 inhibition for currently underserved patients. We are working to rapidly enroll the expansion cohorts in our ongoing Phase 1 study, focused initially on ovarian and breast cancers, while building on our leadership by advancing our highly selective and potent oral CDK7 inhibitor, SY-5609, as our next development candidate."

Dose Escalation Data

The dose escalation portion of the Phase 1 trial characterized the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of SY-1365 in patients with advanced solid tumors to establish a dose and regimen for the expansion portion of the trial. PD assays used to establish proof-of-mechanism included a CDK7 occupancy assay to evaluate SY-1365 binding and a custom gene expression assay to evaluate downstream transcriptional changes in patients. Preliminary anti-tumor activity was also assessed.

Enrollment in the dose escalation portion of the trial was completed in September. In total, 32 patients were treated with SY-1365 as a single agent at doses ranging from 2 mg/m2 to 112 mg/m2 using either a weekly or twice weekly dosing regimen. Patients were treated for three weeks out of each four-week cycle. Patients had a range of solid tumors, the most prevalent being ovarian cancer (eight patients), breast cancer (eight patients) and endometrial cancer (five patients). Patients’ median age was 63 (ranging from 25 to 87), with a median of five prior therapies (ranging from one to 13). As of an October 15th data snapshot, the median treatment duration was 46.5 days (ranging from two to 147 days) and four patients remained on treatment.

Safety

Adverse events (AEs) were predominantly low-grade, reversible and generally manageable.
The most commonly reported AEs were headache, nausea, vomiting and fatigue.
No neutropenia was reported.
Dose-limiting toxicities were headache, coronary vasospasm and fatigue.
A maximum tolerated dose was not defined.
Pharmacokinetics

Plasma PK exposures were linear over the doses tested.
No drug accumulation was observed with repeat dosing.
Proof-of-Mechanism

SY-1365 demonstrated dose-dependent effects on CDK7 occupancy and downstream gene expression changes in blood cells.
At doses of 32 mg/m2 and higher, CDK7 occupancy was greater than 50 percent when measured three days following dose administration, exceeding target occupancy levels in preclinical models that correlated with anti-tumor activity.
CDK7 occupancy in blood cells was similar to target occupancy in tumor tissue biopsies available from two patients in the clinical trial.
Early Signs of Clinical Activity

As of the October 15th data snapshot, clinical activity per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria was observed in seven of the 19 patients (37%) who were evaluable for clinical responses, including:

One patient with ovarian cancer in her fourth relapse who had a confirmed partial response (PR) after two cycles of treatment at the 80 mg/m2 twice-weekly dose. The patient remained in PR at her CT assessment after six cycles and recently entered her seventh month on study treatment.
Six additional patients who had stable disease, lasting between 50 and 127 days. Most of these patients received doses equal to or greater than 32 mg/m2.
Based on these data, Syros selected a twice-weekly dose of 80 mg/m2 of SY-1365 when administered as a single agent, and a once-weekly target dose of 80 mg/m2 of SY-1365 when administered in combination with other agents, for further evaluation in the ongoing Phase 1 expansion cohorts in multiple ovarian and breast cancer patient populations.

Ongoing Expansion of Phase 1 Trial

Upon completing enrollment in the dose-escalation portion of the trial, Syros opened expansion cohorts to further assess the safety and anti-tumor activity of SY-1365 in multiple ovarian and breast cancer patient populations. The initial expansion strategy is based on preclinical data showing anti-tumor activity in these tumor types, a strong mechanistic rationale and high unmet need. The expansion cohorts are evaluating SY-1365: as a single agent in primary platinum-refractory ovarian cancer patients; as a single agent in ovarian cancer patients who have relapsed after three or more therapies; in combination with carboplatin in ovarian cancer patients who have relapsed after one or more prior therapies; and in combination with fulvestrant in patients with hormone-receptor positive (HR+) metastatic breast cancer who have progressed after treatment with a CDK4/6 inhibitor. An additional cohort is enrolling patients with any solid tumor accessible for biopsy to further evaluate the mechanism of action of SY-1365. Additional details about the trial can be found using the identifier NCT03134638 at www.clinicaltrials.gov.

The dose escalation data presented at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) meeting is now available on the Publications and Abstracts section of the Syros website at www.syros.com.

Conference Call and Webcast

Syros will host a conference call today at 4:00 p.m. ET to discuss the data from the dose escalation portion of its Phase 1 trial.

The live call may be accessed by dialing (866) 595-4538 for domestic callers or (636) 812-6496 for international callers and referencing conference ID number: 4567679. A live webcast of the conference call will be available online on the Investors & Media section of the Syros website at www.syros.com. An archived replay of the webcast will be available for approximately 90 days.