On June 3, 2019 Heat Biologics, Inc. (NASDAQ: HTBX), a biopharmaceutical company developing therapies designed to activate a patient’s immune system against cancer, reported compelling new interim results from its ongoing Phase 2 study investigating HS-110 in combination with Bristol-Myers Squibb’s anti-PD-1 checkpoint inhibitor, nivolumab (Opdivo) (Press release, Heat Biologics, JUN 3, 2019, View Source [SID1234536792]). The updated results were obtained from Cohort B patients whose data has matured an additional 3 months since last reported at the ASCO (Free ASCO Whitepaper)-SITC Clinical Immuno-Oncology Symposium in February of this year. This data may represent the first Phase 2 data showing clinical activity in non-small cell lung cancer (NSCLC) patients whose disease has progressed after prior treatment with a checkpoint inhibitor (CPI). The Cohort B results were presented yesterday at the2019American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting poster session.

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COL(ret) George E Peoples, MD, FACS, Heat’s Chief Medical Advisor, noted, "These latest Cohort B data provides us even greater confidence that the addition of HS-110 to nivolumab may restore anti-tumor activity in patients whose disease has progressed after treatment with a CPI. Of particular note, 4 out of 5 evaluable patients in Cohort B with PD-L1 negative tumors achieved disease stabilization and 4 out of 7 evaluable patients with low CD8+ TIL levels in their tumors achieved disease stabilization. We are encouraged by these positive results and look forward to reporting additional data later this year."

Jeff Hutchins, Ph.D., Heat’s Chief Scientific and Operating Officer said, "The fact that we saw tumor shrinkage in 35% of patients and disease control in 55% of patients whose disease has progressed after treatment with a CPI supports our mechanistic hypothesis that the broad, T-cell mediated immune response activated by HS-110 may improve clinical outcomes for patients who have lost the benefit of treatment with a checkpoint inhibitor. It is also important to note that the occurrence of dermal injection site reactions is associated with statistically significant improved progression free survival and overall survival, providing further support for the mechanism of action of HS-110."

Highlights for Cohort B patients arepresented below:

HS-110 in combination with nivolumab demonstrates clinical activity i’difficult to treat’ low CD8+ TIL (≤10%) and PD-L1 negative (<1%) tumors:
4 out of 5 evaluable patients with PD-L1 negative tumors achieved disease stabilization, 1 of which was a RECIST partial response.
4 out of 7 evaluable patients with low CD8+ TIL tumors achieved disease stabilization, 2 of which were RECIST partial responses.
The addition of HS-110 to nivolumab may restore clinical benefit to patients whose disease has progressed after CPI treatment failure:
Tumor shrinkage observed in 35% of patients
Disease control rate of 55%
Median Progression-Free Survival (mPFS) of 2.7 months
Median Overall Survival (mOS) not yet reached
The occurrence of any grade dermal Injection Site Reaction during treatment (Y/N) is associated with improved Progression-Free Survival and Overall Survival:
mPFS: NR vs 1.8 months; HR 0.17 (95% CI, 0.03-0.84); p=0.013
mOS: NR vs 5 months; HR 0.13 (95% CI, 0.02-0.71); p=0.002
Treatment with HS-110 in combination with nivolumab was well tolerated, with no additional toxicities beyond those observed with single agent CPI therapy.

Trial results are summarized in the official 2019 ASCO (Free ASCO Whitepaper)Annual Meeting poster.

Trial Design

The Phase 2 trial is designed to evaluate the safety and efficacy of HS-110 combined with an immune checkpoint inhibitor for the treatment of advanced non-small cell lung cancer. Cohort B consists of patients who received a minimum of 4 months of treatment with a checkpoint inhibitor (CPI) as part of their prior therapy, but subsequently had documented progressive disease. Patients receive weekly HS-110 (1 x 107 cells) administered as 5 intradermal 0.1 mL injections for 18 weeks in combination with bi-weekly nivolumab 240 mg IV administered until confirmed disease progression or unacceptable toxicity, whichever occurs first. The primary endpoint is objective response rate (ORR); secondary endpoints include overall survival (OS), progression-free survival (PFS), disease control rate (DCR) and duration of response (DOR). Exploratory endpoints include correlation of clinical outcomes to baseline CD8+ TILs, PD-L1 expression, peripheral blood tumor mutation burden and ELISPOT analysis.

On June 3, 2019 Novartis reported new data and clinical trial updates in NSCLC at the ASCO (Free ASCO Whitepaper) 2019 Annual Meeting. This includes primary efficacy results from the GEOMETRY mono-1 Phase II clinical trial demonstrating that investigational MET inhibitor capmatinib (INC280) shows promise as a potential treatment option for patients with locally advanced or metastatic NSCLC that harbor MET exon-14 skipping mutation (Press release, Novartis, JUN 3, 2019, View Source [SID1234536809]). There are currently no approved targeted therapies to treat this particularly aggressive form of NSCLC. Results of the Phase II study will be presented at an oral session today at ASCO (Free ASCO Whitepaper), June 3, 2019, at 8:00 a.m. CDT (Abstract #9004)[1].

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GEOMETRY mono-1 is an international, prospective, multi-cohort, non-randomized, open-label study evaluating 97 adult patients with locally advanced or metastatic NSCLC harboring MET exon-14 skipping mutation who received capmatinib tablets 400 mg orally twice daily. Primary efficacy results among treatment-naive patients (Cohort 5b: 28 patients) were a 68% overall response rate (ORR) based on the Blinded Independent Review Committee (BIRC) assessment per RECIST v1.1 (95% CI: (47.6 – 84.1)). Forty-one percent of previously treated NSCLC patients (Cohort 4: 69 patients) also responded (95% CI: (28.9 – 53.1)). Data on median duration of response (DOR), a key secondary endpoint, was 11.14 months (95% CI: (5.55 – NE)) and 9.72 months (95% CI: (5.55 – 12.98)), respectively. Intracranial activity in 54% (n=7/13) of patients, including some cases of complete resolution of brain lesions, was also observed by ad hoc neuro-radiologist review in patients with brain lesions. All results were based on independent assessment by the BIRC, and all tumor CT scans were evaluated in parallel by two radiologists to confirm the response.

The most common treatment related adverse events (AE) (>=10% all grades) across all cohorts (n=334), were peripheral edema (42%), nausea (33%), creatinine increase (20%), vomiting (19%), fatigue (14%), decreased appetite (13%) and diarrhea (11%); the majority of the AEs were grades 1/2.

"New lung cancer treatment options are critical, as this deadly disease affects more than 2 million new patients around the world each year," said John Tsai, MD, Head of Global Drug Development and Chief Medical Officer, Novartis. "The GEOMETRY mono-1 results are encouraging, and we look forward to discussing these results with health authorities with the hope of bringing this targeted treatment option to people with this aggressive type of lung cancer."

Capmatinib Granted Orphan Drug and Breakthrough Therapy Designation Status
The U.S. Food and Drug Administration recently granted capmatinib Breakthrough Therapy Designation for patients with metastatic NSCLC harboring MET exon-14 skipping mutation with disease progression on or after platinum-based chemotherapy. Previously, both the U.S. FDA and Japan’s Pharmaceuticals and Medical Devices Agency recognized capmatinib with Orphan Drug status. It is estimated that 3% to 4% of all patients with NSCLC have an identified MET mutation[3].

"The efficacy observed with capmatinib in the GEOMETRY mono-1 trial is promising," said Juergen Wolf, MD, University Hospital, Cologne. "In addition to positive overall response rate among first-line patients with the MET mutation, the duration for the responses, including the activity in the brain, and capmatinib’s safety profile are important milestones for this patient population. As a group, patients with MET mutated NSCLC often require special clinical considerations, as they are generally older and with poor prognosis further limiting their treatment options."

About GEOMETRY mono-1
GEOMETRY mono-1 is an international, prospective, multi-cohort, non-randomized, open-label Phase II study to evaluate the efficacy and safety of single-agent capmatinib (INC280) in adult patients with EGFR wildtype, ALK-negative rearrangement, advanced NSCLC harboring MET amplification and/or mutations. Patients with locally advanced or metastatic NSCLC harboring MET exon-14 skipping mutation (centrally confirmed) were assigned to Cohorts 4 (previously treated patients) or 5B (treatment-naive), regardless of MET amplification/gene copy number, and received 400 mg capmatinib tablets orally twice daily. The primary endpoint was ORR based on the BIRC assessment per RECIST v1.1. The key secondary endpoint was duration of response (DOR) by the BIRC. The GEOMETRY mono-1 study found an ORR in the treatment-naive patients (n=28) of 67.9% (95% CI: 47.6 – 84.1) and an ORR of 40.6% (95% CI: 28.9 – 53.1) in the previously treated patients (n=69). Median DOR was 11.14 months (95% CI: 5.55-NE) in treatment-naive patients and 9.72 months (95% CI: 5.55-12.98) in previously treated patients[1].

The most common treatment-related AEs included peripheral edema, nausea, creatinine increase and vomiting. Of patients treated with capmatinib, 84% experienced an AE, with 36% having grade 3/4 AEs (only 4.5% were Grade 4)[1].

Capmatinib (INC280) is an investigational, oral and selective MET inhibitor licensed to Novartis by Incyte Corporation in 2009. Under the Agreement, Incyte granted Novartis worldwide exclusive development and commercialization rights to capmatinib and certain back-up compounds in all indications.

Studying Tumor-Promoting Inflammation in Lung Cancer – Ongoing CANOPY Trials
Trials in Progress (TiP) updates on the CANOPY clinical program were also included in the ASCO (Free ASCO Whitepaper) updates. CANOPY is made up of three randomized, double-blind and placebo-controlled Phase III trials evaluating canakinumab (ACZ885), a selective IL-1ß inhibitor (Abstract #TPS9124) [4],[5].

CANOPY-A is a Phase III multicenter, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of canakinumab as adjuvant therapy in adult subjects with stages II-IIIA and NSCLC following complete surgical resection. The primary endpoint is disease-free survival (Abstract #7013).
CANOPY-1 is a randomized, double-blind, placebo-controlled, Phase III study investigating canakinumab versus placebo in combination with platinum-based chemotherapy (CTx) and pembrolizumab in previously untreated patients with stage IIIB/IIC-IV squamous and non-squamous NSCLC. The study will evaluate the incidence of dose-limiting toxicity (DLT) in the first 42 days of treatment, as well as PFS and overall survival (OS).
CANOPY-2 is a randomized, double-blind, placebo-controlled, Phase III study investigating canakinumab or placebo plus docetaxel in stage IIIB-IV NSCLC patients previously treated with PD-1 or PD-L1 inhibitors, as well as CTx. The primary endpoints are incidence of DLT in the first 42 days of treatment and OS.
Novartis Commitment to Lung Cancer
Worldwide, lung cancer causes more deaths than colon, breast and prostate cancer combined, and more than 2 million new cases of lung cancer are diagnosed each year[2]. Despite treatment advances, patients with NSCLC still have a poor prognosis and limited treatment options. This includes the nearly 70% of NSCLC patients who have a genomic mutation that may be targeted with available therapies[6]. To determine the most appropriate treatment, medical organizations recommend genomic testing for patients with lung cancer[7].

Novartis Oncology’s research has helped transform treatment approaches for patients living with NSCLC. Novartis continues its commitment to the global lung cancer community through ongoing studies, as well as the exploration of investigational compounds in NSCLC, including those that target genetic biomarkers and tumor promoting inflammation.

On June 3, 2019 Provectus (OTCQB: PVCT) reported that preliminary safety, response, biomarker, and quality of life results from the Company’s ongoing Phase 1 clinical trial of single agent PV-10 for the treatment of symptomatic neuroendocrine tumors (NET) metastatic to the liver (mNET) were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2019 Annual Meeting, held in Chicago, IL from May 31-June 4, 2019 (Press release, Provectus Biopharmaceuticals, JUN 3, 2019, View Source [SID1234536830]). Intralesional injection of oncolytic immunotherapy PV-10 can yield immunogenic cell death in solid tumor cancers that results in tumor-specific reactivity in circulating T cells.1-5 PV-10 clinical development includes cutaneous melanoma, hepatocellular carcinoma, and metastatic liver cancers such as uveal melanoma in single-agent and combination therapy settings.

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This single-center Phase 1 study is being conducted at The Queen Elizabeth Hospital in Adelaide, Australia to evaluate the potential safety, tolerability, and preliminary efficacy of PV-10 in mNET patients (NCT02693067). The primary endpoint for the trial is safety, and secondary endpoints include objective response rate (ORR) of injected target and measurable bystander lesions, target lesion somatostatin receptor expression, and biochemical response. Six patients in the first cohort each received one percutaneously-administered injection of PV-10 to one target lesion per treatment cycle. Patients in the second cohort can receive PV-10 injection of multiple lesions per cycle (2 of 6 patients in the second cohort have received at least one cycle of PV-10 thus far).

Preliminary Results from the Presentation at ASCO (Free ASCO Whitepaper):

Baseline characteristics (N=6): 67% men; median age of 65 years (range 47-72).

Disease characteristics: primary tumor site – 50% small intestine, 33% pancreas, and 17% caecal; 87% Grade 2 (well differentiated, intermediate); all patients were refractory to systemic somatostatin analogues and peptide receptor radionuclide therapy.

PV-10 treatment summary: Median of 1 cycle (mean 1.7, range 1-4) and median dose per cycle of 2.1 mL (range 1.0-5.8 mL).

Preliminary safety: Acceptable toxicity (e.g., post-procedure pain, carcinoid flare, nausea); liver function tests have remained stable.

Preliminary target lesion efficacy: 50% objective response and 87% disease control; response follow-up in 3 patients (50%) is ongoing

Preliminary patient-level efficacy data were not available at the time of data cutoff.

Preliminary clinical and biomarker outcomes: overall quality of life scores were stable in 5 patients (87%); Chromogranin A responses were stable in 5 patients (87%)

Preliminary changes in peripheral blood mononuclear cells were not available at the time of data cutoff.
Dominic Rodrigues, Vice Chair of the Company’s Board of Directors, said, "Patients with neuroendocrine tumors remain a cancer population with high unmet medical need. This poster describes Provectus’ continued progress towards demonstrating the widespread use of small molecule oncolytic immunotherapy PV-10 for the treatment of immunologically ‘cold’ or non-T cell inflamed tumor types."

Mr. Rodrigues added, "Patients in this study experienced no safety concerns from single or repeated injections of PV-10 into the liver. Furthermore, we believe PV-10 treatment provided in this trial yielded encouraging, preliminary evidence of single-agent drug activity, including both local and systemic disease control."

A copy of the ASCO (Free ASCO Whitepaper) poster presentation is currently available on Provectus’ website at View Source

About Neuroendocrine Tumors

NET associated with the gastrointestinal tract are frequently indolent but troublesome as a result of endocrine secretory properties and a propensity for metastasis to the liver, nodes, and lungs. mNET located in the midgut and liver often secrete vasoactive products, giving rise to "Carcinoid Syndrome" (e.g., flushing, diarrhea, wheezing, abdominal cramps, and peripheral edema).

About PV-10

PV-10 causes acute oncolytic destruction of injected tumors, releasing damage associated molecular pattern molecules (DAMPs) and tumor antigens that initiate an immunologic cascade where local response by the innate immune system facilitates systemic anti-tumor immunity by the adaptive immune system. The DAMP release-mediated adaptive immune response activates lymphocytes, including CD8+ T cells, CD4+ T cells, and NKT cells, based on clinical and preclinical experience in multiple tumor types. T cell function can be further augmented by combining PV-10 with immune checkpoint inhibition.

PV-10 is undergoing clinical study for adult solid tumor cancers like melanoma and cancers of the liver (including metastatic symptomatic neuroendocrine tumors and metastatic uveal melanoma) and preclinical study for pediatric cancers like neuroblastoma5, Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma.

Orphan drug designation status has been granted to PV-10 by the U.S. Food and Drug Administration for the treatments of metastatic melanoma in 2006, hepatocellular carcinoma in 2011, neuroblastoma in 2018, and ocular melanoma (including uveal melanoma) in 2019.

PV-10’s active pharmaceutical ingredient is rose bengal disodium (RB) (4,5,6,7-tetrachloro-2’,4’,5’,7’-tetraiodofluorescein disodium salt), a small molecule halogenated xanthene. PV-10 drug product is a bright rose red solution containing 10% w/v RB in 0.9% saline for injection, which is supplied in single-use glass vials containing 5 mL (to deliver) of solution and administered without dilution to solid tumors via intratumoral injection.

Provectus’ intellectual property includes a family of US and international patents that protect the process by which pharmaceutical grade RB and related xanthenes are produced, reducing the formation of previously unknown transhalogenated impurities that exist in commercial grade RB in uncontrolled amounts. The requirement to identify and control these substances is in accordance with International Conference on Harmonisation (ICH) guidelines for the manufacturing of active pharmaceutical ingredient that is suitable for clinical trial and commercial pharmaceutical use. US patent numbers are 8,530,675, 9,273,022, and 9,422,260; patent expirations range from 2030 to 2031.

On June 3, 2019 Bayer reported results of a new analysis from clinical trials investigating Vitrakvi (larotrectinib) in patients with TRK fusion cancer with primary central nervous system (CNS) tumors or brain metastases (Press release, Bayer, JUN 3, 2019, View Source [SID1234536847]). The analysis included 14 patients with primary CNS tumors evaluable for efficacy, including cases of glioma, glioblastoma, glioneural tumors, and astrocytoma. In this population, Vitrakvi demonstrated an overall response rate (ORR) of 36% (n=5; 95% CI: 13-65), including 14% complete responses (CR, n=2) and 21% partial responses (PR, n=3). The remaining 64% of patients had stable disease and no patients experienced progressive disease as best response based on investigator assessment using RANO (Response Assessment in Neuro-Oncology) and RECIST 1.1 (Response Evaluation Criteria In Solid Tumors). In five evaluable patients with NTRK gene fusion positive solid tumors with brain metastases, the ORR was 60% (n=3 PRs; 95% CI: 15-95) based on investigator assessment and RECIST 1.1. The remaining 40% of patients (n=2) had stable disease.1

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Vitrakvi is indicated for the treatment of adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are either metastatic or where surgical resection will likely result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.2

The analysis included 24 TRK fusion cancer patients with brain metastases or primary CNS tumors who were identified from across three different clinical studies.1 Eighteen patients presented with primary CNS tumors (data cut-off February 19, 2019), of which 14 were evaluable, and six patients had non-primary CNS tumors and brain metastases, of which five were evaluable (data cut-off July 30, 2018).1 The adverse events seen in the presentations were mostly grade 1-2.3,4,5

These data were presented in an oral presentation at ASCO (Free ASCO Whitepaper) on June 3, 2019 (Abstract 2006, Session: Central Nervous System Tumors; Monday, June 3, 3:15PM – 3:27PM CDT, Room: S102).

"These data are important as we continue to see efficacy with Vitrakvi in TRK fusion cancer across different tumor types and ages," said Scott Z. Fields, M.D., Senior Vice President and Head of Oncology Development at Bayer’s Pharmaceuticals Division. "The responses in these patients underscore the importance of widespread genomic cancer testing to identify patients who may be appropriate for this treatment."

Data on Vitrakvi in CNS tumors

A total of 24 patients with intracranial disease were identified from three clinical studies (adult Phase I trial, NCT02122913, 1 patient; Pediatric Phase I/II trial SCOUT, NCT02637687, 12 patients; and the adult/adolescent Phase II basket trial NAVIGATE, NCT02576431, 11 patients).1

About Vitrakvi (larotrectinib)
Vitrakvi is indicated for the treatment of adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are either metastatic or where surgical resection will likely result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment.2 This indication is approved under accelerated approval based on overall response rate and duration of response.2 Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.2

Important Safety Information for VITRAKVI (larotrectinib)

Neurotoxicity: Among the 176 patients who received VITRAKVI, neurologic adverse reactions of any grade occurred in 53% of patients, including Grade 3 and Grade 4 neurologic adverse reactions in 6% and 0.6% of patients, respectively. The majority (65%) of neurologic adverse reactions occurred within the first three months of treatment (range 1 day to 2.2 years). Grade 3 neurologic adverse reactions included delirium (2%), dysarthria (1%), dizziness (1%), gait disturbance (1%), and paresthesia (1%). Grade 4 encephalopathy (0.6%) occurred in a single patient. Neurologic adverse reactions leading to dose modification included dizziness (3%), gait disturbance (1%), delirium (1%), memory impairment (1%), and tremor (1%).2

Advise patients and caretakers of these risks with VITRAKVI. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dose when resumed.2

Hepatotoxicity: Among the 176 patients who received VITRAKVI, increased transaminases of any grade occurred in 45%, including Grade 3 increased AST or ALT in 6% of patients. One patient (0.6%) experienced Grade 4 increased ALT. The median time to onset of increased AST was 2 months (range: 1 month to 2.6 years). The median time to onset of increased ALT was 2 months (range: 1 month to 1.1 years). Increased AST and ALT leading to dose modifications occurred in 4% and 6% of patients, respectively. Increased AST or ALT led to permanent discontinuation in 2% of patients.2

Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed.2

Embryo-Fetal Toxicity: VITRAKVI can cause fetal harm when administered to a pregnant woman. Larotrectinib resulted in malformations in rats and rabbits at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily.2

Advise women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment and for 1 week after the final dose of VITRAKVI.2

Most Common Adverse Reactions (≥20%): The most common adverse reactions (≥20%) were: increased ALT (45%), increased AST (45%), anemia (42%), fatigue (37%), nausea (29%), dizziness (28%), cough (26%), vomiting (26%), constipation (23%), and diarrhea (22%).2

Drug Interactions: Avoid coadministration of VITRAKVI with strong CYP3A4 inhibitors (including grapefruit or grapefruit juice), strong CYP3A4 inducers (including St. John’s wort), or sensitive CYP3A4 substrates. If coadministration of strong CYP3A4 inhibitors or inducers cannot be avoided, modify the VITRAKVI dose as recommended. If coadministration of sensitive CYP3A4 substrates cannot be avoided, monitor patients for increased adverse reactions of these drugs.2

Lactation: Advise women not to breastfeed during treatment with VITRAKVI and for 1 week after the final dose.2

Please see the full Prescribing Information for VITRAKVI (larotrectinib).

About TRK Fusion Cancer
TRK fusion cancer occurs when an NTRK gene fuses with another unrelated gene, producing an altered TRK protein.2 The altered protein, or TRK fusion protein, becomes constitutively active or overexpressed, triggering a signaling cascade.2 These TRK fusion proteins can act as an oncogenic driver, promoting cell proliferation and survival in tumor cell lines, leading to TRK fusion cancer, regardless of where it originates in the body.2 TRK fusion cancer is not limited to certain types of tissues and can occur in any part of the body.6 TRK fusion cancer occurs in various adult and pediatric solid tumors with varying frequency, including lung, thyroid, GI cancers (colon, cholangiocarcinoma, pancreatic and appendiceal), sarcoma, CNS cancers (glioma and glioblastoma), salivary gland cancers (mammary analogue secretory carcinoma) and pediatric cancers (infantile fibrosarcoma and soft tissue sarcoma).2,6

About Oncology at Bayer
Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The oncology franchise at Bayer includes five marketed products and several other assets in various stages of clinical development. Together, these products reflect the company’s approach to research, which prioritizes targets and pathways with the potential to impact the way that cancer is treated.

On June 3, 2019 Aadi Bioscience, Inc. (Aadi), Aadi Bioscience, Inc (Aadi), a privately held clinical stage biopharmaceutical company, reported preliminary data on the ongoing nab-sirolimus (ABI-009) registration trial (AMPECT) for Advanced (metastatic or locally advanced) Malignant PEComa (perivascular epithelioid cell tumor) – a rare form of sarcoma for which there is no currently approved therapy (Press release, Aadi, JUN 3, 2019, View Source [SID1234536913]).

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Nanoparticle albumin-bound sirolimus (nab-Sirolimus), an mTOR inhibitor, received Breakthrough Therapy Designation from the US Food and Drug Administration (FDA) in Dec 2018, "for the treatment of patients with advanced (metastatic or locally advanced) malignant perivascular epithelioid cell tumor (PEComa)."

The AMPECT trial was conducted at 9 U.S. sites and enrolled 34 adult patients, with 31 confirmed as PEComa by a central pathology laboratory. PEComa origin sites in these patients included the uterus, pelvis, retroperitoneum, lung, kidney, liver, brain, muscle, ovary, aorta and small bowel.

These data, demonstrating a 42 percent confirmed investigator-assessed objective response rate (ORR) across advanced PEComas originating in various tissues, were released in an oral presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2019 annual meeting in Chicago (abstract 11005). AMPECT Principal Investigator Andrew Wagner, M.D., Ph.D., from the Dana Farber Cancer Institute, said nab-sirolimus had delivered consistent and durable responses in advanced PEComa patients. "These responses were achieved with a manageable safety profile," Dr. Wagner said. "We saw a majority of the responding patients achieving a response by their first assessment at 6 weeks following initiation of therapy. Cytotoxic chemotherapies and other drugs approved for treatment of advanced sarcomas show only marginal benefit in PEComas. Activation of the mTOR pathway is common in PEComa and case reports have shown activity of mTOR inhibitors [1]. We are encouraged by the outcomes in this first-ever prospective clinical trial in advanced PEComa."

"The Aadi Bioscience team is proud to have contributed to this important study presented at ASCO (Free ASCO Whitepaper)," said Neil Desai, Ph.D., Chief Executive Officer of Aadi Bioscience. "We are grateful to the patients, families, and clinical trial teams who help push the boundaries of available care through their participation in clinical trials. These results are an important milestone in the ongoing development of nab-sirolimus across a wide range of diseases and therapeutic indications that are driven by mTOR activation and for which there is a need for new therapies." Dr. Desai added: "Results from the AMPECT study will serve as the basis for the ABI-009 New Drug Application (NDA) for nab-sirolimus, which the company expects to submit to the FDA in late 2019 or early 2020. The primary analysis for the NDA will rely upon central, independent radiology review, which will be performed in the second half of 2019. The company plans to release these data at a scientific meeting, which will also include additional patient follow-up, before the end of 2019."

Key Data Presented at ASCO (Free ASCO Whitepaper)

The primary efficacy outcome measure for the analysis presented at ASCO (Free ASCO Whitepaper) is investigator-assessed objective response rate (ORR) as measured by RECIST v 1.1. Key secondary endpoints include duration of response (DOR), progression-free survival (PFS), PFS rate at 6 months (PFS6) and safety. The data presented at ASCO (Free ASCO Whitepaper) employed a May 10, 2019 data cut-off, summarized below, was based on response assessments as performed by each respective clinical trial site (local, investigator-assessed radiology). A separate response assessment performed by independent radiologists, not yet completed, will be required to support global regulatory filings.

Consistent with agreements with the FDA, advanced PEComa patients enrolled in the Phase 2 trial (AMPECT) contributed to the efficacy analysis. The data presented are based on 34 patients evaluable for safety and 31 patients evaluable for efficacy per defined criteria in the protocol.

About Aadi Bioscience and nab-sirolimus (ABI-009)

Aadi is a clinical stage biopharmaceutical company led by Dr. Neil Desai, an inventor of ABRAXANE and the albumin-based technology platform. Aadi’s lead product nab-sirolimus (sirolimus albumin-bound nanoparticles for injectable suspension, ABI-009) is an mTOR inhibitor complexed with human albumin that has significantly higher tumor accumulation, mTOR target suppression and improved efficacy over other mTOR inhibitors in preclinical models. mTOR as a therapeutic target is well