On March 18, 2019 Leap Therapeutics, Inc. (Nasdaq:LPTX) reported the presentation of clinical data from its ongoing Phase 2 clinical trial of DKN-01 in patients with advanced gynecological malignancies at the Society of Gynecologic Oncology 50th Annual Meeting on Women’s Cancer (Press release, Leap Therapeutics, MAR 18, 2019, View Source [SID1234534414]). Patients, including those with carcinosarcoma and Wnt pathway alterations, have experienced partial responses and durable clinical benefit in both the monotherapy and combination arms of the study. The complete data set will become available in the coming months as the most recently enrolled patients have yet to be evaluated. The complete poster is available on Leap’s website at View Source

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"We are very pleased with the single agent and combination activity of DKN-01 in this heavily pre-treated population. Allowing patients to achieve partial responses and durable stable disease with a favorable safety profile reflects meaningful clinical benefit," commented Rebecca C. Arend, M.D., Ph.D., Department of Obstetrics and Gynecology at the University of Alabama at Birmingham School of Medicine. "With the rapid enrollment of this study since the beginning of the year, we are looking forward to robust data maturing during the year."

"It is encouraging to see the mechanism-based strategy of enriching the study with patients with Wnt pathway alterations lead to impressive clinical outcomes," commented Michael Birrer, M.D., Ph.D., Director of the Comprehensive Cancer Center at the University of Alabama at Birmingham. "We are also particularly interested in the early activity in carcinosarcoma patients, who are in need of new and better treatment options."

· DKN-01 single agent partial response: Twenty-one patients (who had previously received one to ten lines of therapy) have been enrolled in two monotherapy arms of the study. Twelve patients are currently evaluable. One patient has experienced a partial response (PR), and six patients have had stable disease (SD) for greater than six weeks. Seven patients have been recently enrolled and have not yet had their first imaging assessment. This study marks the third different tumor type where DKN-01 has had single agent activity.

·Partial response and tumor reductions in DKN-01/Paclitaxel combination: Forty-one patients (who had previously received one to nine lines of prior therapy) have been enrolled in two combination arms of the study. Twenty-one patients are currently evaluable. One patient has experienced a PR, and fifteen patients have had SD for greater than six weeks. Thirteen patients have been recently enrolled and have not yet had their first imaging assessment.

·Patients whose tumors had confirmed Wnt pathway alterations experienced a greater duration of clinical benefit: In eight evaluable monotherapy patients with confirmed Wnt pathway alterations, one patient has experienced a PR and four have had SD. In the fourteen evaluable combination therapy patients, one patient has experienced a PR and seven have had SD. The patient with a partial response on DKN-01 combination therapy has a tumor with a CTNNB1 mutation. Tumor CTNNB1 mutations stabilize the transcription factor beta-catenin and are correlated with increased levels of DKK1 and poor clinical outcomes. In this study, eight CTNNB1 patients are evaluable, and six experienced clinical benefit.

· Carcinosarcoma partial response leads to new expansion cohort at higher dose: Carcinosarcoma is a rare and difficult-to-treat form of uterine cancer. Four carcinosarcoma patients have been enrolled, and the three evaluable patients had tumor reductions and one experienced a PR. To explore a new treatment option for these patients, the Company will expand the study and provide a higher dose of DKN-01 as a monotherapy and in combination with paclitaxel.

About P204

The P204 study is a Phase 2 basket study evaluating DKN-01 as a monotherapy and in combination with paclitaxel in patients with relapsed/refractory endometrioid endometrial cancer (EEC) or endometrioid ovarian cancer (EOC). The study contains four groups and is designed to evaluate the efficacy, safety, and pharmacodynamics of DKN-01 monotherapy and combination therapy in both EEC and EOC, with each group following a 2-stage Simon Minimax design. The study will enroll approximately 94 patients, of which approximately 50% will be required to have documented activating mutations of beta-catenin or other Wnt signaling alterations.

About DKN-01

DKN-01 is a humanized monoclonal antibody that binds to and blocks the activity of the Dickkopf-1 (DKK1) protein, a modulator of Wnt/Beta-catenin signaling, a signaling pathway frequently implicated in tumorigenesis and suppressing the immune system. DKK1 has an important role in tumor cell signaling and in mediating an immuno-suppressive tumor microenvironment through enhancing the activity of myeloid-derived suppressor cells and downregulating NK ligands on tumor cells.

On March 18, 2019 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported first results from SAUL, a Phase IIIb study evaluating the safety of Tecentriq in approximately 1000 patients with locally advanced or metastatic urothelial carcinoma (mUC) including several clinically relevant populations reflective of real-world clinical practice (patients with renal impairment, poor performance status (ECOG PS 2), treated asymptomatic CNS metastases, stable controlled autoimmune disease) (Press release, Hoffmann-La Roche, MAR 18, 2019, View Source [SID1234534413]).[1] Data from the study showed that both safety and efficacy, a secondary endpoint, were consistent with previous studies in both the overall population and a subgroup of patients corresponding to the patient population of the pivotal Phase III study, IMvigor211 ("IMvigor211-like"[2]). The SAUL study is ongoing and further subgroup analyses will also be presented at future medical meetings.

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"SAUL is the largest prospective safety study of a cancer immunotherapy in metastatic urothelial carcinoma and provides clinicians with valuable information about Tecentriq in a real-world setting" said Sandra Horning, M.D., Chief Medical Officer and Head of Global Product Development. "We remain committed to improving outcomes for people living with this devastating illness and we look forward to sharing data in the future from our ongoing Phase III studies in early and metastatic disease".

The data presented at EAU show that the safety of the Tecentriq monotherapy treatment was consistent with the known safety profile of the medicine. Grade 3-4 adverse events (AEs) occurred in 43% of the patients, and treatment-related grade ≥3 AEs occurred in 13% of the patients, with most common reported side effects being fatigue, asthenia, colitis and hypertension (each in 1%). AEs leading to treatment discontinuation happened in 6% of the patients. Additionally, the efficacy results, secondary endpoints of the study, showed an overall survival of 10 months (95% CI 8.8–11.9 months) in the IMvigor211-like population. In the overall population, median OS was 8.7 months (95% CI 7.8–9.9). The median duration of follow up was 12.7 months.

These data are being presented today at the annual EAU Congress Breaking News Session at 7:30am CET.

About the SAUL study
The SAUL study is a Phase IIIb, prospective, open label, single arm, multicentre study designed to assess the safety of Tecentriq as a second- to fourth-line treatment for people with locally advanced or metastatic urothelial carcinoma (95%) or non-urothelial carcinoma (5%) of the urinary tract. In addition, the study evaluates the efficacy of Tecentriq and potential tumour biomarkers associated with Tecentriq. It enrolled 1004 people globally, 997 of whom received Tecentriq. IMvigor211-like patients and patients with renal impairment, poor performance status (ECOG PS 2), treated asymptomatic CNS metastases or stable controlled autoimmune disease were eligible. The primary endpoint was safety; secondary endpoints included overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and duration of response (DoR).

A summary of the data is included below:

a Includes but not limited to patients with renal impairment, Eastern Cooperative Oncology Group (ECOG) performance status grade 2, treated asymptomatic central nervous system metastases or stable controlled autoimmune disease
b All patients corresponding to the patient population in the pivotal IMvigor211 (locally advanced or metastatic UC who have progressed during or following a platinum-containing regimen)
*Treatment-related grade 5 AEs (n=7, 0.7%): two cases of dyspnoea, one case each of colitis, intestinal perforation, respiratory failure, chronic kidney disease, drug-induced liver injury.

*Includes but not limited to patients with renal impairment, Eastern Cooperative Oncology Group (ECOG) performance status grade 2, treated asymptomatic central nervous system metastases or stable controlled autoimmune disease.
†Patients corresponding to the patient population in the pivotal IMvigor211 study (locally advanced or metastatic UC who have progressed during or following a platinum-containing regimen)

Tecentriq in genitourinary cancers
Roche has five Tecentriq Phase III studies investigating Tecentriq in different settings and diseases of genitourinary cancers including two Phase III studies in early bladder cancer (IMvigor010) and metastatic bladder cancer (IMvigor130), a Phase III study in metastatic castrate resistant prostate cancer (IMbassador250) and two Phase III studies in renal cell carcinoma (IMmotion151 and IMmotion010). Tecentriq is already approved as a monotherapy for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma: after prior platinum‐containing chemotherapy, or who are considered cisplatin ineligible and whose tumours have a PD-L1 expression ≥5%. The FDA also approved Tecentriq in patients with locally advanced or mUC and ineligible for any platinum-based chemotherapy, irrespective of PD-L1 status.

About Tecentriq
Tecentriq is a monoclonal antibody designed to bind with a protein called PD-L1 expressed on tumour cells and tumour-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, Tecentriq may enable the activation of T cells. Tecentriq has the potential to be used as a foundational combination partner with cancer immunotherapies, targeted medicines and various chemotherapies across a broad range of cancers.

In the United States Tecentriq in combination with nab-paclitaxel is approved for treatment of PD-L1-positive metastatic triple-negative breast cancer; and in combination with Avastin and chemotherapy for the initial treatment of people with metastatic non-squamous NSCLC. In the Europe Union, the non-squamous NSCLC indication includes people with EGFR mutant or ALK genomic tumour aberrations after failure of appropriate targeted therapies. Tecentriq is also approved in the European Union, United States and more than 85 countries for people with previously treated metastatic non-small cell lung cancer (NSCLC) and for certain types of untreated or previously treated metastatic urothelial carcinoma who are not eligible for cisplatin chemotherapy, or who have had disease progression during or following platinum-containing therapy.

About bladder cancer
Bladder cancer is the tenth most common cancer worldwide, with almost 555,000 new cases diagnosed in 2018. [3] It is the sixth most common cancer in men and the 17th most common cancer in women,[3] and the disease is three times more common in developed countries than in less developed countries.[4] There are three types of bladder cancer: transitional cell carcinoma (which begins in cells in the innermost tissue layer), squamous cell carcinoma (which begins in squamous cells) and adenocarcinoma (which begins in glandular cells in the lining of the bladder). Most cancers that form in the bladder are transitional cell carcinomas.[5]

About Roche in cancer immunotherapy
For more than 50 years, Roche has been developing medicines with the goal to redefine treatment in oncology. Today, we’re investing more than ever in our effort to bring innovative treatment options that help a person’s own immune system fight cancer.
By applying our seminal research in immune tumour profiling within the framework of the Roche-devised cancer immunity cycle, we are accelerating and expanding the transformative benefits with Tecentriq to a greater number of people living with cancer. Our cancer immunotherapy development programme takes a comprehensive approach in pursuing the goal of restoring cancer immunity to improve outcomes for patients.

On March 18, 2019 Puma Biotechnology, Inc. (Nasdaq: PBYI) reported that its licensing partner Specialised Therapeutics Asia (STA) has received marketing authorization from Australia’s Therapeutic Goods Administration (TGA) to commercialize NERLYNX (neratinib) in Australia for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer following adjuvant trastuzumab based therapy (Press release, Puma Biotechnology, MAR 18, 2019, View Source [SID1234534408]). STA has submitted regulatory applications to gain approval to introduce NERLYNX in Singapore. Further applications are planned by STA in other countries in South East Asia, including Malaysia, Brunei, Vietnam and Thailand.

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TGA approval was based on the Phase III ExteNET trial, a multicenter, randomized, double-blind, placebo-controlled trial of neratinib following adjuvant trastuzumab treatment. Women (n=2,840) with early-stage HER2-positive breast cancer and within two years of completing adjuvant trastuzumab were randomized to receive either neratinib (n=1420) or placebo (n=1420) for one year.

The results of the ExteNET trial demonstrated that after two years of follow-up, invasive disease-free survival (iDFS) was 94.2% in patients treated with neratinib compared with 91.9% in those receiving placebo (HR 0.66; 95% CI: 0.49, 0.90, p=0.008).

The most common adverse reactions (>5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail disorder, dry skin, abdominal distention, weight loss, and urinary tract infection. The most common adverse reaction leading to discontinuation was diarrhea, which was observed in 16.8% of neratinib-treated patients. Hepatotoxicity or increases in liver transaminases led to drug discontinuation in 1.7% of neratinib-treated patients.

"TGA approval marks the first time Australian women are being presented with an opportunity for extended-adjuvant therapy that will reduce the risk of disease recurrence in patients who would otherwise have had a relapse," said Carlo Montagner, Chief Executive Officer of Specialised Therapeutics. "We are pleased to be at the forefront of this new treatment paradigm and look forward to changing outcomes for these women and their families."

Puma Biotechnology’s CEO and President, Alan H. Auerbach, added, "Reducing the risk of disease recurrence remains a need for patients, despite advances in the treatment of early stage HER2-positive breast cancer. We are pleased that our partner STA will be bringing this new medicine to patients throughout Australia and would like to express our appreciation to the patients, caregivers and physicians who contributed to the neratinib clinical development program and, more specifically, the ExteNET trial. We are committed to continuing to expand NERLYNX accessibility to patients around the world."

About HER2-Positive Breast Cancer

Approximately 20 to 25 percent of breast cancer tumors over-express the HER2 protein. HER2-positive breast cancer is often more aggressive than other types of breast cancer, increasing the risk of disease progression and death. Although research has shown that trastuzumab can reduce the risk of early stage HER2-positive breast cancer returning after surgery, up to 25% of patients treated with trastuzumab experience recurrence.

On March 17, 2019 Oncoceutics, Inc. reported that the latest efficacy data for the use of ONC201 in adult recurrent H3 K27M-mutant glioma will be presented in an Oral Abstract Session at the 2019 Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago (Press release, Oncoceutics, MAR 17, 2019, View Source [SID1234558354]). In addition, there will be an update on ONC201 in previously irradiated pediatric H3 K27M-mutant glioma that will be presented in a poster session.

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The oral abstract session presentation, entitled "Single agent ONC201 in adult recurrent H3 K27M-mutant glioma" will describe the clinical experience of ONC201, in adults with recurrent H3 K27M-mutant glioma. It will be presented on Monday, June 3rd from 9:24 am to 9:36 am (Abstract 3005) as part of the Developmental Therapeutics and Tumor Biology (nonimmune) session by Isabel Arrillaga, MD, PhD, Associate Clinical Director of Neuro-Oncology at MGH Cancer Center. The presentation will discuss a cohort of adults with H3 K27M-mutant glioma patients who have received ONC201 after failure of available therapies. The results will include assessments of radiographic response, progression-free survival, and overall survival, as well as safety and clinical benefit. This presentation was selected for review by a panel of discussants.

A second data set to be presented is entitled "ONC201 in previously-irradiated pediatric H3 K27M-mutant glioma," and will be presented as a poster by Sharon Gardner, MD, Associate Professor in the Department of Pediatrics at NYU Langone Cancer Center, on Saturday, June 1, from 8:00 am to 11:00 am (Abstract 10046, Poster 428). Dr. Gardner will discuss the emerging safety, pharmacokinetics, and outcome data available from the first arm of the first pediatric clinical trial with ONC201. This trial is currently evaluating the compound in children with DIPG, or other forms of H3 K27M-mutant glioma, who have no meaningful treatment options.

"As someone who was involved from the very beginning in Oncoceutics’ development programs, I am delighted to see the progress in the development of ONC201 for brain tumors that have challenged our abilities in oncology for a long time", said Joseph Bertino, MD, FAACR, Founding Member of the Scientific Advisory Board of Oncoceutics, Past President of ASCO (Free ASCO Whitepaper) and AACR (Free AACR Whitepaper), and, amongst the numerous accolades given to him, recipient of the 2018 Award for Lifetime Achievement in Cancer Research. "I am encouraged that the therapeutic concept of addressing GPCRs with imipridones for applications in oncology will materialize as a new paradigm to treat cancer. ONC206 is the next compound from the imipridone portfolio that will enter the clinic, and based on the preclinical profile, including the well characterized binding target and mechanism of action, I expect an efficient translational program."

A team of Oncoceutics team members will be present at the conference. If you have any questions, please contact us at [email protected].

The abstracts are listed below:

Single agent ONC201 in adult recurrent H3 K27M-mutant glioma. Presented Monday, June 3, 2019. View Source
ONC201 in previously-irradiated pediatric H3 K27M-mutant glioma. Presented Saturday, June 1, 2019. View Source

On March 16, 2019 Sotio presented the corporate presentation (Presentation, SOTIO, MAR 16, 2019, View Source [SID1234534547]).

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