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Tarveda Therapeutics Presents Pharmacokinetic and Tumor Biopsy Data from First in Human Study of PEN-866 at the 2020 AACR Virtual Annual Meeting

On April 27, 2020 Tarveda Therapeutics, Inc., a clinical stage biopharmaceutical company developing a new class of potent and selective precision oncology medicines, which it refers to as Pentarin miniature drug conjugates, reported that new pharmacokinetic and target engagement data from its Phase 1 study of PEN-866 in patients with solid tumor malignancies at the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting (Press release, Tarveda Therapeutics, APR 27, 2020, View Source [SID1234556654]). PEN-866 is the initial clinical program from Tarveda’s HSP90 binding miniature drug conjugate platform, and is designed to bind to activated Heat Shock Protein 90 (HSP90) to accumulate and release its potent topoisomerase 1 inhibitor (SN-38) payload in solid tumors. The poster titled, "Characterization of PEN-866, a Heat Shock Protein 90 (HSP90) binding conjugate of SN-38, in patient plasma and tumors from the first in human study", showcased confirmatory pharmacokinetics of PEN-866 in patient plasma and highlighted data from two patient biopsies, which confirmed higher concentrated levels of the PEN-866 conjugate and SN-38 payload in tumor relative to plasma.

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"The plasma pharmacokinetic data from the dose escalation portion of our Phase 1/2a clinical trial demonstrated that PEN-866 exhibited favorable plasma pharmacokinetics as predicted from our preclinical data, with PEN-866 remaining intact while in circulation. Unconjugated SN-38 remained very low at approximately 2% of the PEN-866 exposure in circulation," said Mark Bilodeau, Ph.D., Chief Scientific Officer of Tarveda. "We are also very encouraged by the tumor biopsy data, which showed tumor uptake and retention of PEN-866 as well as the subsequent release of SN-38, which was significantly increased in comparison to the presence of PEN-866 and released SN-38 in plasma at days 1 and 7/8 after dosing. These data are consistent with PEN-866 preclinical data showing materially increased uptake and retention of PEN-866 in the tumor versus untargeted forms of SN-38, such as irinotecan."

Dr. Bilodeau continued, "the preferential tumor targeting and release of SN-38 seen in the tumors with PEN-866 serves as a firm foundation for the broader potential of the platform to produce new HSP90 binding miniature drug conjugates with promising anti-cancer payloads."

"The clinical and preclinical results seen to date show that PEN-866 accumulates and is retained in tumors where it is then released over multiple days at therapeutic levels. This is in contrast to plasma where the conjugate remains intact and is quickly cleared from the circulation, helping to spare potential damage to normal tissue," said Jeffrey Bloss, M.D., Chief Medical Officer of Tarveda. "These data support the miniature conjugate design of PEN-866 and are a contributor to the beneficial therapeutic index seen with PEN-866 in Phase 1. We are excited to work with PEN-866 in Phase 2a and believe its development should be explored as a single agent and in combination with other exciting therapeutics, such as PARP inhibitors and immuno-oncology drugs that have struggled to successfully combine with cytotoxic therapies."

PEN-866 Phase 1 Study Design & Results

Thirty patients with advanced solid tumor malignancies were enrolled in the Phase 1 dose escalation cohorts and received PEN-866 on days 1, 8, and 15 in 28-day cycles over a dose range of 16-228 mg/m2. The PEN-866 plasma concentration profile showed a concentration decline after end of infusion resulting in an average half-life of approximately 7 hours. PEN-866 plasma concentrations up to 39 µg/mL and area under the concentration curve of 57 h·µg/mL were achieved and determined for the recommended Phase 2a dose. Of the 30 patients, two consented to tumor biopsy collection to determine PEN-866 and SN-38 accumulation. Biopsy results from a pancreatic cancer patient who received a 150 mg/m2 dose of PEN-866 showed that PEN-866 and SN-38 levels in the tumor were significantly higher than observed in plasma 24 hours post dose and that the ratio of SN-38 to PEN-866 was high in tumor and low in plasma. Results from a patient with esophageal cancer who received a 175 mg/m2 dose of PEN-866 on day one and underwent tumor biopsy on day seven showed continued exposure of PEN-866 and SN-38 in the tumor. While in the plasma, PEN-866 was extremely low and SN-38 was unmeasurable (on day 8). These biopsy results support previous preclinical data showing that PEN-866 slowly releases its SN-38 payload in the tumor over multiple days.

Overall the data show that PEN-866 demonstrated favorable plasma pharmacokinetics with low levels of SN-38 observed in plasma. More importantly, both the conjugate and released payload (SN-38) were concentrated and retained in the tumor for up to a week. PEN-866 recently completed the Phase 1 all-comers, dose escalation and safety portion of a Phase 1/2a clinical trial. Additional information on the Phase 1/2a clinical trial for PEN-866 is available at clinicaltrials.gov, through identifier number NCT03221400.

NOXXON Presents Latest Clinical Data From the Phase 1/2 NOX-A12 / Keytruda® Combination Trial in Colorectal and Pancreatic Cancer at the AACR Virtual Annual Meeting 2020

On April 27, 2020 NOXXON Pharma N.V. (Paris:ALNOX) (Euronext Growth Paris: ALNOX), a biotechnology company focused on improving cancer treatments by targeting the tumor microenvironment (TME), reported the presentation of the latest clinical results from the Phase 1/2 study with CXCL12 inhibitor, NOX-A12, and pembrolizumab in patients with microsatellite-stable, metastatic colorectal or pancreatic cancer at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting 2020 (Press release, NOXXON, APR 27, 2020, View Source [SID1234556652]). The data were presented in a short video with commentary by the first author, Dr. Niels Halama, from the National Center for Tumor Diseases (NCT) in Heidelberg, Germany.

The data indicate that treatment with NOX-A12 plus pembrolizumab in the combination therapy part of the study resulted in stable disease in 25% of patients and prolonged time on treatment vs. prior therapy for 35% of patients. The safety profile of the combination therapy was consistent with that of pembrolizumab in advanced cancer patients. Comparison of tumor biopsies from before and after NOX-A12 monotherapy showed a trend towards agglomeration of T cells within tumors in about half of the patients where NOX-A12 had induced a Th1-type cytokine response. This agglomeration was accompanied by reduced distances between T cells and cancer cells, suggesting increased infiltration of effector immune cells into tumor tissue and a more effective immune response.

"Based on the fact that these indications have so far remained unaffected by checkpoint inhibitors, the outcome of this trial emphasizes the real potential NOX-A12 has on targeting the tumor microenvironment and enabling the intended mode of action of pembrolizumab," said Aram Mangasarian, CEO of NOXXON. "These results provide a strong rationale for moving this program forward into a larger scale randomized trial with a less-advanced patient population, an opportunity we intend to pursue with a partner."

"As a clinician who has worked with colorectal and pancreatic cancer patients, the data provide signals that support the potential impact of the combination of NOX-A12 with pembrolizumab, which is a significant step for these cancers with extremely limited options," commented Dr. Jarl Ulf Jungnelius, CMO of NOXXON.

Access to AACR (Free AACR Whitepaper) Virtual Annual Meeting 2020 is freely available upon registration. NOXXON’s abstract and a short video with commentary (presentation CT117) are now available online in the Virtual Poster Session section VPO.CT01 on the AACR (Free AACR Whitepaper) website, as well as on the NOXXON website.

RGENIX Presents Initial Results of Combination Trial of RGX-104 at the 2020 AACR Annual Meeting

On Aprii 27, 2020 RGENIX, Inc., a clinical stage biopharmaceutical company developing first-in-class small molecule and antibody cancer therapeutics, reported it is presenting an abstract on RGX-104, RGENIX’s lead therapy in development. RGENIX’s abstract, "RGX-104, a first-in-class immunotherapy targeting the liver-X receptor (LXR); Initial results from the phase 1b RGX-104 plus Docetaxel combination dose escalation cohorts" was accepted for the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, which this year was scheduled as two virtual meetings (Press release, Rgenix, APR 27, 2020, View Source [SID1234556651]). The abstract results will be presented as a virtual poster presentation (CT-146) during the VPO.CT01 – Phase I Clinical Trials session on April 27, by clinical investigator Dr. Emerson Lim from Columbia University Herbert Irving Comprehensive Cancer Center, who is lead author on the study.

For the dose escalation stage of this Phase 1b study, RGX-104 was tested in combination with docetaxel across three different dose escalation cohorts. The presentation will outline the safety profile, pharmacodynamic effects, and clinical activity of the combination in unselected heavily pre-treated patients with refractory or relapsed solid tumors. The results support further development of this regimen.

RGX-104 is a small-molecule LXR agonist that modulates innate immunity via transcriptional activation of the ApoE gene. RGX-104 inhibits tumor angiogenesis and depletes myeloid derived suppressor cells (MDSC), thereby activating cytotoxic T-lymphocytes. MDSCs are associated with resistance to both checkpoint inhibitors (CPI) and chemotherapy, including docetaxel, providing a rationale for combination therapy with RGX-104. Consistent with this, RGX-104 plus docetaxel combination therapy is highly efficacious in pre-clinical models that demonstrate MDSC-associated docetaxel resistance.

As of February 7, 2020, 11 patients with refractory solid tumors were treated with the combination across 3 different dosing cohorts. The safety profile was consistent with the individual profiles of RGX-104 and docetaxel, with neutropenia the most common drug-related adverse event observed, but dose-limiting in only one patient in cohort one, where RGX-104 was administered at 80mg BID every day with docetaxel administered at 35mg/m2 weekly x 3. In cohorts two and three, in which patients received RGX-104 dosing five consecutive days out of seven (at either 80mg or 100mg BID) and a reduced dose of docetaxel (28mg/m2), no dose-limiting toxicity was observed, and sustained pharmacodynamic activity (ApoE activation and MDSC depletion) was achieved. The overall response rate (ORR) in all evaluable patients was 22%, with a disease control rate (DCR) of 56%. Across cohorts 2 and 3, where target RGX-104 pharmacodynamic effects were achieved, the ORR was 33% with a 67% DCR. Clinical responses included partial responses (PRs) in CPI refractory/resistant patients, including an ongoing confirmed PR in a CPI resistant melanoma patient treated in cohort 2 that remains on study at 10 months. Clinical activity was associated with increases in T cell activation markers exceeding that generally observed with RGX-104 alone.

As a result, the RGX-104/docetaxel regimen is being evaluated in a phase 1b/2 expansion study that has begun enrolling patients with relapsed/refractory extensive stage small-cell lung cancer (ES-SCLC) or high grade-neuroendocrine tumors (HG-NET).

Emerson Lim, M.D., principal investigator from Columbia University Herbert Irving Comprehensive Cancer Center and lead author and presenter of the poster, said, "The clinical activity seen in the dose escalation of RGX-104 combined with Docetaxel is quite encouraging; especially notable is the ongoing PR of greater than 10 months duration in a patient with metastatic melanoma who had previously progressed with combination Nivolumab and Ipilimumab as his second line therapy. I am hopeful this combination will provide a therapeutic option for patients with ES-SCLC/HG-NET as currently being tested in the expansion phase."

RGX-104 is also being evaluated in combination with the front-line standard-of-care regimen of pembrolizumab plus carboplatin/pemetrexed in a phase 1b/2 study currently enrolling patients with advanced non-squamous non-small cell lung cancer (NSCLC).

Masoud Tavazoie, M.D., Ph.D., and Chief Executive Officer of RGENIX, said, "The data from the RGX-104/docetaxel combination dose escalation cohorts are encouraging, providing early safety and efficacy data that support further development of the combination. Though we are still in the early stages of the RGX-104 Phase 1b/2 studies, the results show the potential of RGX-104 to provide durable clinical activity in refractory patients through a novel mechanism-of-action. We look forward to sharing additional findings from these ongoing studies."

AIVITA Biomedical Presents Updates from Ongoing Ovarian Cancer and Glioblastoma Clinical Studies at 2020 AACR Virtual Annual Meeting

On April 27, 2020 AIVITA Biomedical, Inc., a biotechnology company specializing in innovative cell therapy applications, reported that updates from ongoing clinical trials in ovarian cancer and glioblastoma were presented as part of the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting I (Press release, AIVITA Biomedical, APR 27, 2020, View Source [SID1234556649]).

The presentation from Daniela Bota, MD, Ph.D., of the University of California, Irvine, and principal investigator of the Phase 2 clinical trial of AV-GBM-1 in newly diagnosed glioblastoma, included data obtained through March 2020. The study has completed enrollment, and the treatment has been well-tolerated to date with encouraging preliminary survival data.

The presentation from Lisa Abaid, MD, principal investigator of the Phase 2 clinical trial of AVOVA-1 in advanced ovarian cancer, showed the trial is progressing as planned and the treatment has been well-tolerated. Enrollment for the study continues for both tumor collection and randomization.

"We’re encouraged by the progress we’ve made in our clinical programs and the positive tolerability that our patient-specific cancer vaccines have shown so far," said Hans Keirstead, Ph.D., chief executive officer of AIVITA. "We look forward to completing enrollment in our Phase 2 ovarian cancer study and further explore the promising survival data we’ve seen in our Phase 2 glioblastoma study."

The presentations will be available on the AACR (Free AACR Whitepaper) website site at www.aacr.org.

About AIVITA’S Clinical Trials

OVARIAN CANCER

AIVITA’s ovarian Phase 2 double-blind study is active and enrolling approximately 99 patients who are being randomized in a 2:1 ratio to receive either the autologous tumor-initiating cell-targeting immunotherapy or autologous monocytes as a comparator.

Patients eligible for randomization and treatment will be those (1) who have undergone debulking surgery, (2) for whom a cell line has been established, (3) who have undergone leukapheresis from which sufficient monocytes were obtained, (4) have an ECOG performance grade of 0 or 1 (Karnofsky score of 70-100%), and (5) who have completed primary therapy. The trial is not open to patients with recurrent ovarian cancer.

For additional information about AIVITA’s AVOVA-1 trial, patients can visit: www.clinicaltrials.gov/ct2/show/NCT02033616

GLIOBLASTOMA

AIVITA’s glioblastoma Phase 2 single-arm study is active and is enrolling approximately 55 patients to receive the tumor-initiating cell-targeting immunotherapy.

Patients eligible for treatment will be those (1) who have recovered from surgery such that they are about to begin concurrent chemotherapy and radiation therapy (CT/RT), (2) for whom an autologous tumor cell line has been established, (3) have a Karnofsky Performance Status of > 70, and (4) have undergone successful leukapheresis from which peripheral blood mononuclear cells (PBMC) were obtained that can be used to generate dendritic cells (DC). The trial is not open to patients with recurrent glioblastoma.

For additional information about AIVITA’s AV-GBM-1 trial please visit: www.clinicaltrials.gov/ct2/show/NCT03400917

MELANOMA

AIVITA’s melanoma Phase 1B open-label, single-arm study will establish the safety of administering anti-PD1 monoclonal antibodies in combination with AIVITA’s tumor-initiating cell-targeting immunotherapy in patients with measurable metastatic melanoma. The study will also track efficacy of the treatment for the estimated 14 to 20 patients. This trial is not yet open for enrollment.

Patients eligible for treatment will be those (1) for whom a cell line has been established, (2) who have undergone leukapheresis from which sufficient monocytes were obtained, (3) have an ECOG performance grade of 0 or 1 (Karnofsky score of 70-100%), (4) who have either never received treatment for metastatic melanoma or were previously treated with enzymatic inhibitors of the BRAF/MEK pathway because of BRAF600E/K mutations, and (5) are about to initiate anti-PD1 monotherapy.

Takeda Announces U.S. FDA Breakthrough Therapy Designation for Mobocertinib (TAK-788) for the Treatment of NSCLC Patients with EGFR Exon 20 Insertion Mutations

On April 27, 2020 Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) ("Takeda") reported that the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for its investigational drug mobocertinib (TAK-788) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy (Press release, Takeda, APR 27, 2020, View Source [SID1234556648]). There are currently no approved therapies designed to treat this specific form of NSCLC. Mobocertinib is a small-molecule tyrosine kinase inhibitor (TKI) designed to selectively target EGFR and human EGFR 2 (HER2) exon 20 insertion mutations.

The Breakthrough Therapy Designation is based on the overall response rate (ORR) and the long-term benefit seen in patients who responded in a Phase 1/2 study evaluating the safety and efficacy of mobocertinib in patients with locally advanced or metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations and have been previously treated with systemic chemotherapy. This signals a potential advancement in addressing the needs of patients for whom no targeted therapies exist and current treatment options provide limited benefit.

"We are pleased that the FDA has recognized the therapeutic potential mobocertinib offers for patients with EGFR exon 20 insertion-mutant NSCLC who are desperately in need of effective treatment options," said Christopher Arendt, Head, Oncology Therapeutic Area Unit, Takeda. "At Takeda, we are committed to developing novel medicines for hard-to-treat diseases. Establishing Breakthrough Therapy Designation for mobocertinib is one step forward in our efforts to help change the current standard of care for this underserved population."

"Although most EGFR mutations can be targeted by currently available TKIs, people with exon 20 insertion mutations often suffer and feel forgotten since available EGFR inhibitors don’t work well in their cancer," said Jill Feldman, Lung Cancer Patient, Advocate, and Co-Founder of the EGFR Resisters. "We are excited by the potential this treatment has to extend the lives of people who have had no approved treatment options to target their disease."

Breakthrough Therapy Designation from the U.S. FDA is granted to accelerate the development and regulatory review of investigational drugs that are intended to treat serious or life-threatening ailments. Agents with this designation have shown preliminary clinical evidence that indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

Takeda will present for the first time the development of mobocertinib, including the first public disclosure of the structure, during the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting I in a New Drugs on the Horizon session on Tuesday, April 28, from 11:14-11:34 a.m. ET.

About EGFR Exon 20 Insertion-Mutant NSCLC

NSCLC is the most common form of lung cancer, accounting for approximately 85% of the estimated 1.8 million new cases of lung cancer diagnosed each year worldwide, according to the World Health Organization.1,2 Patients with EGFR exon 20 insertion mutations make up only about 1-2% of patients with NSCLC.3,4 This disease carries a worse prognosis than other EGFR mutations because there are currently no FDA-approved therapies that target exon 20 mutations, and current EGFR TKIs and chemotherapy provide limited benefit for these patients.

About Mobocertinib (TAK-788)

Mobocertinib is a potent, small-molecule TKI specifically designed to selectively target EGFR and HER2 exon 20 insertion mutations. In 2019, the U.S. FDA granted mobocertinib Orphan Drug Designation for the treatment of lung cancer with HER2 mutations or EGFR mutations including exon 20 insertion mutations.

Results from the ongoing Phase 1/2 trial of mobocertinib, which is evaluating the efficacy and safety of mobocertinib at 160 mg once daily in previously treated patients with EGFR exon 20 insertions, showed mobocertinib yielded a median progression-free survival (PFS) of 7.3 months and a confirmed overall response rate (ORR) of 43% (n=12/28) in patients with locally advanced or metastatic EGFR exon 20 insertion-mutant NSCLC. The safety profile of mobocertinib was manageable (N= 72). The most common treatment-related adverse events (AEs) were diarrhea (85%), nausea (43%), rash (36%), vomiting (29%) and decreased appetite (25%). These results were presented at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

The mobocertinib development program began in the NSCLC population and is expected to expand to additional underserved populations in other tumor types. Mobocertinib is an investigational drug for which efficacy and safety have not been established.

Takeda in Lung Cancer

Takeda is dedicated to expanding treatment options in the ALK+ NSCLC and EGFR/HER2 insertion-mutant NSCLC treatment landscapes. Our comprehensive programs include the following clinical trials to continue to address unmet needs for people living with lung cancer:

Mobocertinib:

Phase 1/2 study evaluating the safety, pharmacokinetics and antitumor activity of oral EGFR/HER2 inhibitor mobocertinib in patients with NSCLC. This trial has completed enrollment.
Phase 2 EXCLAIM, pivotal extension cohort of the Phase 1/2 trial, which was designed to evaluate the efficacy and safety of mobocertinib at 160 mg once daily in previously treated patients with EGFR exon 20 insertion mutations. This trial has completed enrollment.
Phase 3 EXCLAIM-2, global, randomized study evaluating the efficacy of mobocertinib as a first-line treatment compared to platinum-based doublet chemotherapy in treatment-naïve patients with locally advanced or metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations. This trial is now enrolling.
Phase 1, open-label, multicenter, dose-escalation study evaluating the safety, tolerability and pharmacokinetics of mobocertinib in Japanese patients with locally advanced or metastatic NSCLC. This trial has completed enrollment.
Phase 2 J-EXCLAIM, open-label, multicenter, study evaluating the efficacy of mobocertinib as a first-line treatment in Japanese patients with locally advanced or metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations. This trial is now enrolling.
Phase 1, open-label, multicenter, drug-drug interaction study of mobocertinib and midazolam, a sensitive CYP3A substrate, in patients with advanced NSCLC. This trial is now enrolling.
ALUNBRIG, a next-generation TKI designed to target and inhibit ALK molecular alterations:

Phase 1/2 trial, which was designed to evaluate the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of ALUNBRIG. This trial has completed enrollment.
Pivotal Phase 2 ALTA trial investigating the efficacy and safety of ALUNBRIG at two dosing regimens in patients with ALK+ locally advanced or metastatic NSCLC who had progressed on crizotinib. This trial has completed enrollment.
Phase 3 ALTA-1L, global, randomized trial assessing the efficacy and safety of ALUNBRIG in comparison to crizotinib in patients with ALK+ locally advanced or metastatic NSCLC who have not received prior treatment with an ALK inhibitor. This trial has completed enrollment.
Phase 2 J-ALTA, single-arm, multicenter trial in Japanese patients with ALK+ NSCLC, focusing on patients who have progressed on alectinib. This trial has completed enrollment.
Phase 2 ALTA 2, global, single-arm trial evaluating ALUNBRIG in patients with advanced ALK+ NSCLC who have progressed on alectinib or ceritinib. This trial has completed enrollment.
Phase 3 ALTA 3, global randomized trial comparing the efficacy and safety of ALUNBRIG versus alectinib in participants with ALK+ NSCLC who have progressed on crizotinib. This trial is now enrolling.
For additional information on the mobocertinib and ALUNBRIG clinical trials, please visit www.clinicaltrials.gov.

Takeda’s Commitment to Oncology

Our core R&D mission is to deliver novel medicines to patients with cancer worldwide through our commitment to science, breakthrough innovation and passion for improving the lives of patients. Whether it’s with our hematology therapies, our robust pipeline, or solid tumor medicines, we aim to stay both innovative and competitive to bring patients the treatments they need. For more information, visit www.takedaoncology.com.