On December 11, 2019 Seattle Genetics, Inc. (Nasdaq:SGEN) reported positive pivotal data from the HER2CLIMB trial evaluating tucatinib in patients with HER2-positive metastatic breast cancer (MBC) were presented at the 2019 San Antonio Breast Cancer Symposium (SABCS) and simultaneously published in the New England Journal of Medicine(NEJM) (Press release, Seattle Genetics, DEC 11, 2019, View Source [SID1234552265]). The HER2CLIMB trial compared tucatinib in combination with trastuzumab and capecitabine to trastuzumab and capecitabine alone in patients with unresectable locally advanced or metastatic HER2-positive breast cancer. Patients had previously received trastuzumab, pertuzumab and ado-trastuzumab emtansine (T-DM1). Patients had received a median of four prior lines of therapy overall and three lines in the metastatic setting. Forty-seven percent of the patients enrolled in the trial had brain metastases at the time of enrollment. HER2CLIMB is the first randomized pivotal trial completed to enroll patients with metastatic HER2-positive breast cancer who have untreated or previously treated and progressing brain metastases. Tucatinib is an oral, small molecule tyrosine kinase inhibitor (TKI) that is highly selective for HER2.

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"Following progression on trastuzumab, pertuzumab and T-DM1 in the metastatic HER2-positive breast cancer setting, there is no single standard of care regimen and clinical trial participation is often strongly encouraged. There is a significant unmet medical need for these patients, particularly those who develop brain metastases," said Rashmi Murthy, MD, MBE, Assistant Professor, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. "The addition of tucatinib to the commonly used combination of trastuzumab and capecitabine improved overall survival, reducing the risk of death by 34 percent compared to trastuzumab and capecitabine alone. The results from HER2CLIMB demonstrate tucatinib has the potential to become a new treatment option for patients who have been previously treated with multiple anti-HER2 agents, including patients with and without brain metastases."

"Continued innovation to bring new therapies for the treatment of metastatic HER2-positive breast cancer is urgently needed, and we are encouraged by the impressive clinical activity demonstrated with the addition of tucatinib to trastuzumab and capecitabine in the HER2CLIMB trial," said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics. "Tucatinib demonstrated a statistically significant and clinically meaningful benefit in overall survival, progression-free survival and objective response rate compared to the control arm. We plan to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration and a Marketing Authorization Application (MAA) to the European Medicines Agency by the first quarter of 2020, with the goal of bringing a much-needed new medicine to patients."

Data presented at SABCS and published in NEJM include the primary endpoint of progression-free survival (PFS) as assessed by blinded independent central review (BICR) in the first 480 patients enrolled in the trial. HER2CLIMB enrolled a total of 612 patients to support the analyses of key secondary endpoints, including overall survival (OS) as well as progression-free survival (PFS) in patients with brain metastases at baseline.

Pivotal HER2CLIMB Trial Results

Efficacy:

The primary endpoint of PFS showed that the addition of tucatinib was superior to trastuzumab and capecitabine alone, with a 46 percent reduction in the risk of disease progression or death (hazard ratio (HR)=0.54 [95% Confidence Interval (CI): 0.42, 0.71]; p<0.00001).
Estimated PFS at one year was 33 percent (95% CI: 27, 40) in the tucatinib arm, compared to 12 percent (95% CI: 6, 21) in the trastuzumab and capecitabine arm (control arm).
Median PFS was 7.8 months (95% CI: 7.5, 9.6) in the tucatinib arm, compared to 5.6 months (95% CI: 4.2, 7.1) in the control arm.
The addition of tucatinib to trastuzumab and capecitabine prolonged OS, a key secondary endpoint, reducing the risk of death by 34 percent (HR=0.66 [95% CI: 0.50, 0.88]; p=0.0048), compared to the control arm.
Estimated OS at two years was 45 percent (95% CI: 37, 53) in the tucatinib arm, compared to 27 percent (95% CI: 16, 39) in the control arm.
Median OS was 21.9 months (95% CI: 18.3, 31.0) in the tucatinib arm, compared to 17.4 months (95% CI: 13.6, 19.9) in the control arm.
For patients with brain metastases at baseline, a key secondary endpoint, the tucatinib arm also demonstrated superior PFS compared to trastuzumab and capecitabine alone. Findings demonstrated that the tucatinib regimen resulted in a 52 percent reduction in the risk of disease progression or death, compared to the control arm (HR=0.48 [95% CI: 0.34, 0.69]; p<0.00001).
The estimated PFS at one year was 25 percent (95% CI: 17, 34) with the tucatinib regimen, compared to zero percent in the control arm.
Median PFS was 7.6 months (95% CI: 6.2, 9.5) in the tucatinib arm, compared to 5.4 months (95% CI: 4.1, 5.7) in the control arm.
The confirmed objective response rate (ORR) in the patient population with measurable disease at baseline (511/612) was 40.6 percent (95% CI: 35.3, 46.0) in the tucatinib arm, compared with 22.8 percent (95% CI: 16.7, 29.8) for trastuzumab and capecitabine alone (p=0.0008).
Safety:

Tucatinib in combination with trastuzumab and capecitabine was generally well tolerated. The most common adverse events occurring in more than 20 percent of patients in the tucatinib arm vs. the control arm included: diarrhea (80.9 vs. 53.3 percent), palmar-plantar erythrodysaesthesia syndrome (PPE) (63.4 vs. 52.8 percent), nausea (58.4 vs. 43.7 percent), fatigue (45.0 vs. 43.1 percent) and vomiting (35.9 vs. 25.4 percent), which were primarily low grade.
Discontinuation of tucatinib and placebo due to adverse events was 5.7 percent in the tucatinib arm and 3.0 percent in the control arm.
Greater than or equal to Grade 3 diarrhea was seen in 12.9 percent of the patients in the tucatinib arm vs. 8.6 percent in the control arm. Antidiarrheal prophylaxis was not required per protocol. Antidiarrheals were used in less than half of all cycles where diarrhea was reported. In both treatment arms, when used, the duration of antidiarrheal treatment was short (median of 3 days/cycle).
Greater than or equal to Grade 3 aspartate aminotransferase (AST) was seen in 4.5 percent of the patients in the tucatinib arm vs. 0.5 percent in the control arm, and alanine aminotransferase (ALT) elevation in 5.4 percent vs. 0.5 percent, respectively. Discontinuations due to liver transaminase elevations were infrequent in both arms (ALT: 1.0 vs. 0.5 percent; AST: 0.7 vs. 0.5 percent).
About HER2-Positive Breast Cancer

Patients with HER2-positive breast cancer have tumors with high levels of a protein called human epidermal growth factor receptor 2 (HER2), which promotes the aggressive spread of cancer cells. An estimated 271,270 new cases of invasive breast cancer will be diagnosed in the U.S. in 2019.1 Between 15 and 20 percent of breast cancer cases worldwide are HER2-positive.2 Historically, HER2-positive breast cancer tends to be more aggressive and more likely to recur than HER2-negative breast cancer.2, 3, 4 In patients with metastatic breast cancer, the most common site of first metastasis is in bone, followed by lung, brain, and liver.5, 6 Up to 50 percent of metastatic HER2-positive breast cancer patients develop brain metastases over time.2, 7 Despite recent treatment advances, there is still a significant need for new therapies that can impact metastatic disease, especially brain metastases. There are currently no approved therapies demonstrating progression-free survival or overall survival benefit for the treatment of patients with HER2-positive metastatic breast cancer after progression on T-DM1.8, 9, 10

About HER2CLIMB

HER2CLIMB is a multinational randomized (2:1), double-blind, placebo-controlled, active comparator, pivotal clinical trial comparing tucatinib in combination with trastuzumab and capecitabine compared with trastuzumab and capecitabine alone in patients with locally advanced unresectable or metastatic HER2-positive breast cancer who were previously treated with trastuzumab, pertuzumab and T-DM1. The primary endpoint of the trial was PFS per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as determined by blinded independent central review (BICR) in the first 480 patients enrolled in the trial. HER2CLIMB enrolled a total of 612 patients to support the analyses of key secondary endpoints, including overall survival, PFS per BICR in patients with brain metastases at baseline and confirmed objective response rate. Safety data were evaluated throughout the study.

About Tucatinib

Tucatinib is an investigational, orally bioavailable, potent tyrosine kinase inhibitor that is highly selective for HER2 without significant inhibition of EGFR. Inhibition of EGFR has been associated with significant toxicities, including skin rash and diarrhea. Tucatinib has shown activity as a single agent and in combination with both chemotherapy and other HER2 targeted agents such as trastuzumab.1,2 Studies of tucatinib in these combinations have shown activity both systemically and in brain metastases. HER2 is a growth factor receptor that is overexpressed in multiple cancers, including breast, colorectal and gastric cancers. HER2 mediates cell growth, differentiation and survival. Tucatinib has been granted orphan drug designation by the FDA for the treatment of breast cancer patients with brain metastases.

In addition to HER2CLIMB, tucatinib is being evaluated in a randomized, double-blind, placebo-controlled, multi-center phase 3 trial of tucatinib in combination with T-DM1 compared to T-DM1 alone, in patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including those with brain metastases, who have had prior treatment with a taxane and trastuzumab. The primary endpoint is progression-free survival per RECIST criteria. Secondary endpoints include overall survival, objective response rate and duration of response. The trial is being conducted in North America and is expected to enroll approximately 460 patients. More information about the phase 3 trial, including enrolling centers, is available at www.clinicaltrials.gov.

Tucatinib is also being evaluated in a multi-center, open-label, single-arm phase 2 clinical trial known as MOUNTAINEER, which is evaluating tucatinib in combination with trastuzumab in patients with HER2-positive, RAS wildtype metastatic or unresectable colorectal cancer. The primary endpoint of the trial is objective response rate by RECIST criteria. Progression-free survival, duration of response, overall survival and safety and tolerability of the combination regimen are secondary objectives. Results for 26 patients were evaluated in an analysis and presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2019 Congress. Enrollment is ongoing. More information about the MOUNTAINEER trial, including enrolling centers, is available at www.clinicaltrials.gov.

On December 11, 2019 PharmaCyte Biotech (OTCQB: PMCB) reported that it has a clinical trial product, a clinical trial protocol, including a clinical trial design, a Principal Investigator, and the company is ready to present its treatment for locally advanced, inoperable pancreatic cancer (LAPC) to the U.S. FDA in an effort to secure approval to begin a Phase 2b clinical trial in LAPC (Press release, PharmaCyte Biotech, DEC 11, 2019, View Source [SID1234552264]).

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LAPC is a hard-to-treat disease that leaves patients with very little hope after first-line therapies, Abraxane plus gemcitabine or FOLFIRINOX, no longer offer any benefit to this patient population. The company’s Chief Operating Officer, Dr. Gerald W. Crabtree, said of this group of patients, "Here we have a cadre of patients that are virtually untreatable. They respond to a certain degree to first-line treatment and then can no longer respond, and there they sit with very little option for further response."

However, hope, in the form of a unique live-cell encapsulation technology, could very well be on the way for patients who are stricken with LAPC if the FDA approves PharmaCyte’s Investigational New Drug application (IND). Pancreatic cancer is usually only controllable through removal by surgery and only if found before it has spread to other parts of the body or other organs. PharmaCyte’s treatment, which consists of its signature live-cell encapsulation technology, Cell-in-a-Box, plus low doses of the chemotherapy drug ifosfamide, has already proven in earlier Phase 1 and Phase 2 clinical trials that it can be effective in doing just that—shrinking tumors to the point that they become operable.

Commenting on those earlier trials, PharmaCyte’s Chief Executive Officer, Kenneth L. Waggoner, said, "What’s unique about our therapy is looking back at the earlier clinical trials, patients that had stage 4 metastatic pancreatic cancer had their tumors go from inoperable to operable."

PharmaCyte plans to conduct a Phase 2b clinical trial with a treatment that uses genetically engineered cells to treat cancer. Those cells have been engineered to produce an enzyme, which is normally produced in the patient’s liver, that will convert ifosfamide from its inactive form to its active form. Essentially what patients with LAPC can expect from PharmaCyte’s treatment is that it diverts the conversion of ifosfamide from the patient’s liver, where normal conversion takes place, to the 300 Cell-in-a-Box capsules, which contain a total of about 6.6 million live cells located in the blood supply to the pancreas and whose job it is to "wake up" the non-active drug right at the site of a patient’s tumor.

PharmaCyte’s Chief Scientific Officer, Prof. Dr. Walter H. Günzburg, says, "We’ll be placing those 300 capsules angiographically into the pancreas just upstream of the tumor. The idea being that blood will then come in, bring the non-active prodrug, ifosfamide, to the capsules, and the drug will then be converted inside the capsules to its active form and the prodrug will stream directly into the tumor, so this gives the highest possible concentration of the tumor killing drug actually at the site of the tumor."

For patients suffering from LAPC, this treatment is great news because a much smaller dose of the cancer-killing drug means that it’s a targeted chemotherapy with little to no side effects. Dr. Günzburg added, "We’re converting the drug at the site of the tumor so that patients will experience a very high anti-tumor kill and a very low systemic toxicity."

Dr. Crabtree, who was part of the team at Bristol-Myers Squibb that brought the highly successful cancer drug Taxol (paclitaxel) to market, said, "I’ve been in the cancer business for 50 years, and I’ve been involved in developing a lot of decent drugs—some very good drugs—and worked with some very good people, and this technology to me has been a revelation. It’s completely different from anything else that I have ever experienced, and to me, it presents an absolute new way to treat a very difficult to treat tumor.

"Here we have a chance to have very good results with minimal side effects. In the cancer business, you can’t ask for more than that."

The pancreatic cancer community should be anxiously awaiting PharmaCyte’s submission of its IND to the FDA and the subsequent days following as everyone waits patiently for the FDA to approve what could be a landmark clinical trial in LAPC.

To learn more about PharmaCyte’s pancreatic cancer treatment and how it works inside the body to treat locally advanced inoperable pancreatic cancer, watch the company’s documentary video complete with medical animations at: View Source

On December 11, 2019 Kite, a Gilead Company (Nasdaq: GILD), and Kiniksa Pharmaceuticals, Ltd. (Nasdaq: KNSA) ("Kiniksa") reported that the companies have entered into a clinical collaboration to conduct a Phase 2, multicenter study of mavrilimumab, an investigational fully human monoclonal antibody that targets granulocyte macrophage colony stimulating factor receptor alpha (GM-CSFRα), in combination with Yescarta (axicabtagene ciloleucel) in patients with relapsed or refractory large B-cell lymphoma (Press release, Kite Pharma, DEC 11, 2019, View Source [SID1234552263]). The objective of the study is to determine the effect of mavrilimumab on the safety of Yescarta. Kite will be the sponsor of this study and will be responsible for its conduct.

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"We were excited to present data from several abstracts at the recent ASH (Free ASH Whitepaper) meeting that build upon our understanding of the efficacy and safety profile of Yescarta and we are committed to the exploration of new approaches and treatment combinations that further optimize outcomes for patients," said Christi Shaw, Chief Executive Officer of Kite. "We look forward to working with Kiniksa to learn more about the potential impact of GM-CSFRα inhibition with mavrilimumab."

"The clinical collaboration with Kite furthers Kiniksa’s goal to develop life-changing medicines for patients with significant unmet medical need," said Sanj K. Patel, Chief Executive Officer and Chairman of the Board of Kiniksa. "We believe the potential for GM-CSFRα inhibition to advance the clinical profile for CAR T cell therapy speaks to the potential broad utility of mavrilimumab."

Treatment related induction of GM-CSF has been identified through clinical, translational and preclinical studies as a potential key signal associated with side effects of chimeric antigen receptor T (CAR T) cell therapy. Preclinical evidence shows the potential for interruption of GM-CSF signaling to disrupt CAR T cell mediated inflammation without disrupting anti-tumor efficacy.

Yescarta was the first CAR T cell therapy to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, and high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma. The Yescarta U.S. Prescribing Information has a BOXED WARNING for the risks of cytokine release syndrome and neurologic toxicities; see below for Important Safety Information.

Mavrilimumab, alone or in combination with other therapies such as Yescarta, is investigational and has not been approved by the FDA or any regulatory authority for any uses. Efficacy and safety have not been established.

About Mavrilimumab

Mavrilimumab is an investigational fully-human monoclonal antibody that is designed to antagonize GM-CSF signaling by binding to the alpha subunit of the GM-CSF receptor. Kiniksa is developing mavrilimumab for the potential treatment of giant cell arteritis (GCA), a chronic inflammatory disease of medium to large arteries.

U.S. Important Safety Information for Yescarta

BOXED WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving Yescarta. Do not administer Yescarta to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving Yescarta, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with Yescarta. Provide supportive care and/or corticosteroids as needed.
Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta REMS.
CYTOKINE RELEASE SYNDROME (CRS): CRS occurred in 94% of patients, including 13% with ≥ Grade 3. Among patients who died after receiving Yescarta, 4 had ongoing CRS at death. The median time to onset was 2 days (range: 1-12 days) and median duration was 7 days (range: 2-58 days). Key manifestations include fever (78%), hypotension (41%), tachycardia (28%), hypoxia (22%), and chills (20%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Ensure that 2 doses of tocilizumab are available prior to infusion of Yescarta. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for 4 weeks after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab or tocilizumab and corticosteroids as indicated.

NEUROLOGIC TOXICITIES: Neurologic toxicities occurred in 87% of patients. Ninety-eight percent of all neurologic toxicities occurred within the first 8 weeks, with a median time to onset of 4 days (range: 1-43 days) and a median duration of 17 days. Grade 3 or higher occurred in 31% of patients. The most common neurologic toxicities included encephalopathy (57%), headache (44%), tremor (31%), dizziness (21%), aphasia (18%), delirium (17%), insomnia (9%) and anxiety (9%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events including leukoencephalopathy and seizures occurred with Yescarta. Fatal and serious cases of cerebral edema have occurred in patients treated with Yescarta. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of neurologic toxicities. Monitor patients for signs or symptoms of neurologic toxicities for 4 weeks after infusion and treat promptly.

YESCARTA REMS: Because of the risk of CRS and neurologic toxicities, Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta REMS. The required components of the Yescarta REMS are: Healthcare facilities that dispense and administer Yescarta must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after Yescarta infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense or administer Yescarta are trained about the management of CRS and neurologic toxicities. Further information is available at www.YESCARTAREMS.com or 1-844-454-KITE (5483).

HYPERSENSITIVITY REACTIONS: Allergic reactions may occur. Serious hypersensitivity reactions including anaphylaxis may be due to dimethyl sulfoxide (DMSO) or residual gentamicin in Yescarta.

SERIOUS INFECTIONS: Severe or life-threatening infections occurred. Infections (all grades) occurred in 38% of patients, and in 23% with ≥ Grade 3. Grade 3 or higher infections with an unspecified pathogen occurred in 16% of patients, bacterial infections in 9%, and viral infections in 4%. Yescarta should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after Yescarta infusion and treat appropriately. Administer prophylactic anti-microbials according to local guidelines. Febrile neutropenia was observed in 36% of patients and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids and other supportive care as medically indicated. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

PROLONGED CYTOPENIAS: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Yescarta infusion. Grade 3 or higher cytopenias not resolved by Day 30 following Yescarta infusion occurred in 28% of patients and included thrombocytopenia (18%), neutropenia (15%), and anemia (3%). Monitor blood counts after Yescarta infusion.

HYPOGAMMAGLOBULINEMIA: B-cell aplasia and hypogammaglobulinemia can occur. Hypogammaglobulinemia occurred in 15% of patients. Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following Yescarta treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during Yescarta treatment, and until immune recovery following treatment.

SECONDARY MALIGNANCIES: Patients may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following Yescarta infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

ADVERSE REACTIONS: The most common adverse reactions (incidence ≥ 20%) include CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections-pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias.

On December 11, 2019 Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, reported that it has opened for enrollment a Phase 1b expansion cohort of its ongoing clinical trial evaluating TK216, a first-in-class, targeted, investigational small-molecule inhibitor of the E26 transformation-specific (ETS) family of oncoproteins, in patients with relapsed or refractory Ewing sarcoma (Press release, Oncternal Therapeutics, DEC 11, 2019, View Source [SID1234552262]).

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The decision to open an expansion cohort was based on favorable interim results from the dose-finding cohort of the trial, including a deep and sustained clinical response reported for one of the patients treated at the current, highest exposure dose regimen, who is without evidence of Ewing sarcoma after more than eight months on study and has tolerated treatments with TK216, alone and in combination with vincristine, well. TK216 has been generally well tolerated in this trial. Dose limiting toxicities consisted of transient and manageable myelosuppression, primarily neutropenia.

The expansion cohort will further evaluate the recommended Phase 2 dose regimen of TK216 (200 mg/m2/day for 14 days) in combination with vincristine and is anticipated to enroll approximately 18 patients with relapsed or refractory Ewing sarcoma.

"We are encouraged by the initial clinical activity demonstrated by TK216 in the dose-finding portion of this clinical trial in patients with relapsed/refractory Ewing sarcoma and look forward to further evaluating the recommended Phase 2 dose regimen of TK216 in a larger number of patients with this devastating disease," said James Breitmeyer, M.D., Ph.D., Oncternal’s President and CEO. "This first-in-class targeted investigational agent may also be applicable in other malignancies driven by ETS alterations including acute myeloid leukemia (AML) and prostate cancer, which we continue to explore in preclinical studies."

About TK216

TK216 is an investigational, potentially first-in-class, targeted small-molecule inhibitor of the E26 transformation-specific (ETS) family of oncoproteins including fusion proteins. Tumorigenic fusion proteins involving the EWS protein and an ETS protein can be found in most cases of Ewing sarcoma. ETS-related translocations or overexpression are also found in many other tumors such as prostate cancer and acute myeloid leukemia (AML). TK216 was developed based on discoveries in the laboratory of Jeffrey Toretsky, M.D., at Georgetown Lombardi Comprehensive Cancer Center, who discovered inhibitors of EWS-FLI1 using a novel chemical screening assay. In preclinical models, TK216 was observed to bind to EWS-FLI1, blocking the interaction between this fusion protein and other transcriptome proteins such as RNA helicase A, leading to tumor cell apoptosis and inhibiting tumor growth in animal models. The U.S. Food and Drug Administration (FDA) has granted Orphan Designation and Fast Track designation to TK216 for the treatment of Ewing sarcoma. TK216 is an investigational medication that has not been approved by the FDA for any indication.

About the Study

TK216 is being evaluated in a Phase 1 clinical study as a single agent and in combination with vincristine in patients with relapsed or refractory Ewing sarcoma, a rare pediatric cancer with no standard treatment available after first-line chemotherapy. The dose-finding portion of the study has been completed, and Oncternal is actively enrolling patients in an expansion cohort to evaluate the clinical response of treatment with TK216 in combination with vincristine using the recommended Phase 2 dosing regimen. This multi-center study is actively enrolling patients at seven clinical trial centers across the U.S. Additional information about the TK216 study may be accessed at ClinicalTrials.gov (NCT02657005).

On December 11, 2019 Arrowhead Pharmaceuticals Inc. (NASDAQ: ARWR) reported that it has submitted an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA) for a Phase 1b adaptive dose-finding clinical study of ARO-HIF2, the company’s investigational RNA interference (RNAi) therapeutic being developed as a treatment for patients with clear cell renal cell carcinoma (ccRCC) (Press release, Arrowhead Pharmaceuticals, DEC 11, 2019, View Source [SID1234552261]).

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Javier San Martin, M.D., chief medical officer at Arrowhead, said: "ARO-HIF2 is Arrowhead’s first TRiM enabled investigational RNAi therapeutic to target a cell type outside of the liver. Clear cell renal cell carcinoma, or ccRCC, is one of the most common forms of kidney cancer. Most patients with ccRCC have a mutation in the Von Hippel-Lindau gene, rendering them unable to degrade HIF-2α, which leads to accumulation during tumor hypoxia and promotes tumor growth. We believe this makes HIF-2α an attractive target for an RNAi-based intervention."

Pending regulatory review, the company intends to initiate AROHIF21001 (NCT04169711), a Phase 1b adaptive design dose-finding clinical study in patients with advanced ccRCC to evaluate the safety of ARO-HIF2 and to determine the recommended Phase 2 dose. Additional secondary objectives include the assessment of pharmacokinetics and efficacy, based on Response Evaluation Criteria in Solid Tumors (RECIST). An exploratory objective for AROHIF21001 will be gene target knockdown using tumor biopsy.