On June 3, 2019 BioInvent International AB (OMXS: BINV) reported the submission to the U.S. Food and Drug Administration (FDA) of an Investigational New Drug (IND) application for a Phase I/IIa clinical trial of an immune-modulatory anti-FcγRllB antibody in combination with an anti-PD1 antibody in solid tumors (Press release, BioInvent, JUN 3, 2019, View Source [SID1234536820]).

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The anti-FcγRllB antibody is part of BioInvent’s FcγRIIB-targeting program, which has emerged from its F.I.R.S.T platform technology. It simultaneously identifies both targets and high-quality antibodies that bind to them, generating potentially promising new drug candidates.

"There is a strong rationale to improve the therapeutic efficacy of anti-PD1 antibodies, and this study with our first-in-class monoclonal antibody offers the opportunity to improve treatment of solid cancers. It is a further example of how BioInvent’s platform is producing novel immunoregulatory antibody-based cancer therapies which broaden our own pipeline and offer additional licensing and partnering opportunities" says BioInvent’s CEO Martin Welschof.

The Phase I/IIa study is one of four new clinical programs in solid cancers that the Company intends to initiate. These also include BI-1607 (an anti-FcγRllB antibody) in combination with a checkpoint inhibitor; BI-1808 (an anti-TNFR2 antibody); and the collaboration with Transgene to develop oncolytic viruses encoding a validated anti-CTLA-4 antibody.

About BioInvent

On June 3, 2019 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 [SID1234536839]).

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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.

Enrolled Patients with Confirmatory Response Data Available (n = 31)
Objective Response Rate
(ORR = all PRs) 42% (95% CI: 25% – 61%)
Stable Disease 35%
Disease Control Rate (PR+SD) 77%
Progressive Disease 23%

Sixty-two percent of patients (8/13) with responses are continuing on treatment which include 3 patients on therapy for more than 1 year and 3 patients on therapy for more than 2 years. Median DOR has not been reached; median time to response is 1.4 months (95% CI: 1.3, 2.7). Median PFS is 8.4 months (95% CI: 5.5, –), PFS rate at 3 months (PFS3) is 80% (95% CI: 60%, 90%), PFS6 is 61% (95% CI: 41%, 76%), and 32 percent of all patients enrolled remain on treatment.

For reference, per a meta-analysis of 10 years of phase 2 trials in advanced soft tissue sarcomas (STS) published by the EORTC STS and Bone Sarcoma Group [2], the PFS3 and PFS6 are widely accepted as a meaningful measure of activity of drugs in STS and may be utilized to determine acceptable criteria of benefit. Drugs yielding a PFS rate of ≥40% at 3 months and ≥14% at 6 months are considered to be ‘potentially active’ in advanced STS [2].

A protocol prespecified exploratory mutational and biomarker analysis was available for 25 patients on the AMPECT trial. Mutational status of the suspect genes TSC1 or TSC2 in the mTOR pathway were analyzed for association with patient response outcomes. Mutation or deletion of TSC1 or TSC2 (no overlap) occurred in 5 (20%) and 9 (36%) patients respectively, while 11 (44%) patients had no alterations in TSC1 or TSC2. Responses occurred in 9/9 (100%) patients with TSC2 mutations, 1/5 (20%) patients with TSC1 mutations and 1/11 (9%) of patients with no mutations in TSC1 or TSC2.

The safety data presented at ASCO (Free ASCO Whitepaper) was available for all 34 patients treated on the AMPECT trial. The most common treatment-related hematologic adverse events of any grades included anemia (47%) and thrombocytopenia (32%) and the most common nonhematologic treatment-related adverse events of any grades included mucositis (74%), rash (65%), fatigue (59%), nausea (47%), and diarrhea (38%). Most of these events were grade 1 and 2, were manageable with dose modifications and no grade 4 events were observed. Twelve patients (35%) required dose reductions due to adverse events. Two patients (6%) discontinued nab-sirolimus due to an adverse event.

The AMPECT Phase 2 registration trial for Advanced Malignant Perivascular Epithelioid Cell Tumors completed enrollment in late 2018. Aadi previously received agreement from the FDA that this open label study in approximately 30 efficacy evaluable patients with a primary endpoint of independently reviewed objective response rate could support the submission of an NDA for approval to treat this rare disease.

On June 3, 2019 Constellation Pharmaceuticals, Inc. (Nasdaq: CNST), a clinical-stage biopharmaceutical company using its expertise in epigenetics to discover and develop novel therapeutics, reported the presentation of updated interim data from MANIFEST, the Company’s Phase 2 clinical trial of CPI-0610 in MF (Press release, Constellation Pharmaceuticals, JUN 3, 2019, View Source [SID1234536803]). The interim data, which highlight the tolerability and potentially disease-modifying activity of CPI-0610, were presented in a poster at the annual meeting of the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago.

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"We are excited by these interim data from the MANIFEST trial, which indicate that CPI-0610 is generally well-tolerated and showed signs that it is an active therapeutic agent for the treatment of myelofibrosis, both as a monotherapy and in combination with a standard-of-care JAK inhibitor," said Adrian Senderowicz, M.D., Chief Medical Officer at Constellation Pharmaceuticals. "Moreover, as these data highlight improvements across key hallmarks of myelofibrosis, we believe that CPI-0610 has the potential to address a broad range of unmet needs in patients with this difficult-to-treat cancer. We look forward to the continued evaluation of CPI-0610 in this ongoing Phase 2 trial and to providing additional data from MANIFEST later this year."

The data were gathered from 44 patients enrolled as of April 17, 2019. Twelve patients received 24-week assessments and 16 patients received 12-week assessments. Below is a summary of results from the interim update across primary and secondary endpoints from the trial:

14 of 16 evaluable patients demonstrated spleen volume reductions. Overall, the median best on-trial spleen volume change from baseline was -19.2%.

Of these 16 evaluable patients, 11 were evaluable for improvement in Total Symptom Score (TSS) according to the Myelofibrosis Symptom Assessment Form, Version 4.0. Six of the 11 (55%) evaluable patients achieved greater than 50% TSS improvement from baseline as a best response.

All of these 16 patients were evaluable for Patient Global Impression of Change (PGIC). Fifteen of 16 (94%) evaluable patients reported improvements in PGIC, of which 10 reported feeling either "much improved" or "very much improved" and no patients reported feeling worse following treatment.

Of 12 evaluable patients who received at least 24 weeks of treatment, three were severely anemic and dependent on red-blood-cell transfusions at baseline. Of these three patients, two converted to transfusion independence. These two patients have remained transfusion independent for more than 69 and 24 weeks, respectively, as of April 17, 2019, and remain on trial.

Ten patients were evaluable for bone marrow fibrosis, of which six (60%) experienced improvement in bone marrow morphology of at least one point on a scale of 0-3. Four of these six patients exhibited improvements within six months of starting CPI-0610 therapy.
Based on the interim data, CPI-0610 was generally well-tolerated, both as a monotherapy and in combination with ruxolitinib. Overall, the most commonly reported side effects (≥10%) were diarrhea, vomiting, upper respiratory tract infection, headache, epistaxis, fatigue, dysgeusia, cough and pruritis. Grade 3 or greater treatment-emergent adverse events were only reported in the combination arm, and those reported in more than one patient included thrombocytopenia, anemia, and decreased platelet counts, each of which was reported in two patients. There was one patient death, which the Company assessed as unlikely to have been related to CPI-0610. The combination therapy of CPI-0610 and ruxolitinib showed a non-cumulative, manageable, and mostly reversible asymptomatic thrombocytopenia.

Each of the first four patients enrolled in MANIFEST, of which two received CPI-0610 as a monotherapy and two received CPI-0610 in combination with ruxolitinib, remained on therapy and had been treated for approximately 16 and 20 months, respectively, as of April 17, 2019.

Please see the poster in the Investors & Media section of Constellation’s website for additional details.

As previously announced in November 2018, Constellation expanded the MANIFEST trial to include a third cohort, designed to evaluate CPI-0610 in combination with ruxolitinib as a first-line therapy in JAK-inhibitor-naïve patients with advanced MF. The Company has begun treating patients in this arm of the trial and expects to provide initial results from this cohort, as well as additional data from the ruxolitinib-resistant and -refractory (second-line) cohorts, in the fourth quarter of 2019.

Investor Event

Constellation will host an analyst/investor meeting, with an accompanying conference call and webcast, to discuss this interim update in the Jackson Park D room at Hyatt Regency McCormick Place in Chicago at 8:00 AM EDT/7:00 AM CDT on June 4, 2019. The agenda of the meeting will include:

An overview of myelofibrosis (MF) and the potential impact of Constellation’s BET inhibitor CPI-0610 in treating MF
A review of the interim data from the MANIFEST clinical trial presented in a poster at ASCO (Free ASCO Whitepaper) on June 3
A panel discussion with two key opinion leaders in MF:
Dr. Srdan Verstovsek, a medical oncologist at the University of Texas MD Anderson Cancer Center and an investigator in the MANIFEST trial; and
Dr. Raajit Rampal, a hematologic oncologist at Memorial Sloan Kettering Cancer Center
The event will be webcast live and can be accessed on the Investor Relations section of Constellation’s website at View Source Participants may also access the event and participate in the live question-and-answer session by dialing (877) 473-2077 (domestic) or (661) 378-9662 (international) and referring to conference ID 1295319.

Medical Presentation at EHA (Free EHA Whitepaper)

Dr. Ronald Hoffman of Mt. Sinai Health System, an investigator in the MANIFEST trial, will make an oral presentation on this interim update of MANIFEST at the European Hematology Association (EHA) (Free EHA Whitepaper) annual meeting at 12:15 PM CEST/6:15 AM EDT on June 15, 2019. Slides from the presentation will be posted to Constellation’s website.

About MANIFEST

MANIFEST is an open-label Phase 2 clinical trial of CPI-0610 in patients with myelofibrosis (MF), a rare cancer of the bone marrow that disrupts the body’s normal production of blood cells. Constellation is evaluating CPI-0610, either as a monotherapy or in combination with ruxolitinib, in a second-line setting in patients with MF who are refractory to or intolerant of or have relapsed or lost response to ruxolitinib. Patients in the two second-line arms are being stratified based on transfusion-dependent status. The primary endpoint for the cohorts with transfusion-dependent patients is conversion to transfusion independence for 12 consecutive weeks. The primary endpoint for the patients who were not transfusion-dependent at baseline is spleen volume reduction. In addition, the Company added a third arm designed to evaluate treatment with CPI-0610 in combination with ruxolitinib as a first-line therapy in JAK-1/2-inhibitor-naïve MF patients.

On June 3, 2019 Oncology Venture A/S ("OV" or "the Company") reported that the FDA has given its initial response to the Company’s IND application and proposed pivotal Phase 3 study of LiPlaCis in the US (Press release, Oncology Venture, JUN 3, 2019, View Source [SID1234536822]). The FDA has requested some additional testing of the LiPlaCis related to the product characterization. Oncology Venture expects to have these additional tests completed in good time before initiation of the study. Oncology Venture will in parallel modify the study design to accommodate FDA’s recommendation for the pivotal study. The earlier communicated timeline for the development of the LiPlaCis is unchanged.

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The LiPlaCis pivotal Phase 3 study in the US will, in similarity to the ongoing Danish Phase 2 trial evaluate LiPlaCis and its companion diagnostic LiPlaCis-DRP for the treatment of metastatic breast cancer. The protocol will be upgraded from a single arm study to a randomized study and the number of patients is expected to be around 200 as previously communicated. The new design is also expected to comply with the requirements that the European Medicines Agency, EMA, has on registrational studies.

LiPlaCis is an intelligent, target controlled liposome formulation of one of the world’s most widely used chemotherapies, cisplatin. The specific LiPlaCis formulation allows delivery of LiPlaCis directly at tumor site. Oncology Ventures drug specific diagnostic tool DRP selects the patients whom are expected to benefit from the treatment. LiPlaCis is showing promising results in an ongoing Phase 2 study in patients with metastatic breast cancer.

"As expected, there will always be questions to a registrational study. Upon the useful feedback from the FDA we will design a randomized study, and we are confident that we can deliver the requested product characterization information allowing us to keep the timelines. The ongoing Phase 2 study in Denmark is showing strong results. The OV team has taken advantage of the DRP technology as a differentiating factor and moved this project forward from a phase 1 study to a registrational study in only two years," says Peter Buhl Jensen, M.D., CEO of Oncology Venture.

For further information, please contact:

For investor inquiries
Ulla Hald Buhl, IR & Communications
E-mail: [email protected]
Telephone +45 21 70 10 49 For media inquiries
Thomas Pedersen, Carrotize PR & Communications
E-mail: [email protected]
Telephone +45 60 62 93 90

On June 3, 2019 Rainier Therapeutics, Inc., a privately held clinical stage drug development company, reported the first interim analysis results from its ongoing FIERCE-22 trial of vofatamab in patients with metastatic bladder cancer (Press release, Rainier Therapeutics, JUN 3, 2019, View Source [SID1234536840]). Results were presented at the 2019 American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

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FIERCE-22 is a Phase 1b/2 trial evaluating vofatamab, a FGFR3-targeted antibody, in combination with pembrolizumab, an immune checkpoint inhibitor, to determine safety, tolerability and preliminary efficacy in the treatment of patients with locally advanced or metastatic bladder cancer who have progressed following platinum-based chemotherapy and who have not received prior immune checkpoint inhibitor therapy.

The first interim analysis included data from 28 patients enrolled in the Phase 2 trial, which has a targeted total enrollment of approximately 74 patients. Results demonstrate that treatment with vofatamab and pembrolizumab was well tolerated. Five patients discontinued the study due to treatment emergent adverse events, none related to vofatamab. No dose reductions of vofatamab occurred.

An overall best response rate of 36 percent (8/22) was observed in patients with lesions evaluable by RECIST1.1 criteria, 7/22 (32%) were confirmed. Response rates were similar in both wild type and mutant fusion patients (33% and 43%, respectively). A majority of patients have received at least 8 cycles of therapy (1 cycle=21 days). Responses were notably increased in patients with luminal biology (6 of 9 patients). Paired biopsy data from this trial were recently presented at AACR (Free AACR Whitepaper) "Frontiers in Bladder Cancer" (see poster) showing vofatamab induced immune and inflammatory changes in patients with responses.

"These data provide very encouraging clinical evidence of the effect of vofatamab, an antibody targeted against both wild type and mutated FGFR3, in combination with pembrolizumab. Earlier results from this biopsy-driven trial suggested these responses in the wild type FGFR3 patient cohort occurred in urothelial cancers of luminal subtype which typically have immunologically cold tumors. Biopsies obtained post lead-in treatment with vofatamab showed upregulation of genes associated with an inflammatory response," said Arlene O. Siefker-Radtke, MD, The University of Texas MD Anderson Cancer Center. "Further studies are needed to understand the impact of FGFR3 inhibition in urothelial cancer."

"The evidence demonstrated vofatamab provided similar clinical benefits in these patients regardless of FGFR3 tumor status. We plan to continue the enrollment of both wild-type and mutant/fusion patients, and to complete the ongoing Phase 2 trial," said Esteban Abella, MD, Chief Medical Officer of Rainier Therapeutics.

In addition, results were presented from the Phase 2 portion of the FIERCE-21 trial evaluating vofatamab in combination with docetaxel and vofatamab as monotherapy in patients with locally advanced or metastatic bladder cancer with FGFR3 mutations or gent fusions who have relapsed after or are refractory to at least one prior line of chemotherapy. Data presented indicated vofatamab alone and in combination was well tolerated, with no observed long-term safety issues. Vofatamab monotherapy demonstrated single-agent activity in heavily pre-treated patients. In addition, a substantial portion of patients demonstrated long-term benefit from monotherapy and combination therapy.

About Vofatamab

Vofatamab (formerly B-701) is an antibody specifically targeted against the fibroblast growth factor receptor 3 (FGFR3), a known driver of bladder and potentially other FGFR-driven cancers. Vofatamab is the most advanced targeted antibody specific for FGFR3 known by Rainier Therapeutics to be in clinical development. Vofatamab is currently being evaluated in two clinical trials: FIERCE-22 and FIERCE-21.