On September 30, 2019 AVEO Oncology (NASDAQ: AVEO) reported that it has initiated enrollment in an open-label, multi-center Phase 1b/2 clinical trial evaluating FOTIVDA (tivozanib), the Company’s once-daily, potent and selective vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI), in combination with IMFINZI (durvalumab), AstraZeneca’s human monoclonal antibody directed against programmed death-ligand 1 (PD-L1), in patients with hepatocellular carcinoma (HCC) who have not received prior systemic therapy (Press release, AVEO, SEP 30, 2019, View Source [SID1234539950]).

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The study is expected to enroll approximately 50 patients. The Phase 1b portion will evaluate the safety, tolerability, dose limiting toxicity, maximum tolerated dose and preliminary anti-tumor activity starting with 1.0mg of tivozanib for 21 days followed by 7 days rest together with 1500mg of durvalumab every 28 days. Assuming satisfactory completion of the Phase 1b portion of the study, a Phase 2 expansion cohort will enroll at the dose schedule designated in Phase 1b. The primary outcome measure is incidence of treatment emergent adverse events. Secondary outcome measures include objective response rate per RECIST 1.1, progression free survival, duration of response, and overall survival. The trial is being conducted as part of a clinical collaboration between AVEO and AstraZeneca. AVEO is serving as the study sponsor, with study costs shared equally by both parties and clinical drug supplied by each respective company.

"HCC is the fastest rising cause of cancer-related death in the U.S., driven by prevalent diseases that include hepatitis B and C, nonalcoholic steatohepatitis and obesity. With five-year survival at approximately 26%, there remains a desperate need for new therapeutic options," said Michael Bailey, president and chief executive officer of AVEO. "VEGF TKIs and immunotherapy represent current standard of care monotherapies for advanced HCC, and we believe that the combination of tivozanib and durvalumab, both of which have demonstrated single agent activity in HCC, holds great promise as a potential new treatment option for this patient population. Tivozanib’s unique tolerability profile has the potential to make it an attractive VEGF TKI to combine with immunotherapy; in collaboration with AstraZeneca, we look forward to elucidating the potential of the tivozanib-durvalumab combination in patients with previously untreated advanced liver cancer."

About Tivozanib

Tivozanib (FOTIVDA) is an oral, once-daily, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) approved for the treatment of adult patients with advanced renal cell carcinoma (RCC) in the European Union plus Norway, New Zealand and Iceland. It is a potent and selective inhibitor of all three VEGF receptors.1,2 Tivozanib has been shown to significantly reduce regulatory T-cell production in preclinical models3 and has demonstrated synergy in combination with nivolumab (anti PD-1) in a Phase 2 study in RCC4. Tivozanib has been investigated in several tumor types, including renal cell, hepatocellular, colorectal, ovarian and breast cancers.

About Durvalumab

Durvalumab (IMFINZI) is a human monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80, countering the tumor’s immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi is also approved for previously-treated patients with advanced bladder cancer in 10 countries, including the US.

As part of a broad development programme, Imfinzi is also being tested as a monotherapy and in combination with tremelimumab, an anti-CTLA4 monoclonal antibody and potential new medicine, as a treatment for patients with NSCLC, small cell lung cancer, bladder cancer, head and neck cancer, liver cancer, cervical cancer, biliary tract cancer and other solid tumours.

On September 30, 2019 MiNA Therapeutics, the pioneer in RNA activation (RNAa) therapeutics, reported final Phase 1 clinical data of MTL-CEBPA as a single agent in patients with advanced liver cancer as well as pre-clinical data demonstrating synergistic immunological and anti-tumour activity of MTL-CEBPA in combination with anti-PD1 checkpoint inhibition (Press release, MiNA Therapeutics, SEP 30, 2019, View Source [SID1234539949]). The data will be presented in two posters at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2019 Congress taking place in Barcelona, Spain on September 28th and September 30th.

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"In addition to the ongoing evaluation of MTL-CEBPA in combination with sorafenib in patients with advanced liver cancer, the new pre-clinical findings support investigating MTL‑CEBPA and anti-PD1 checkpoint combination therapy in patients with other solid tumour cancers."

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"The Phase 1 study, in which immunological activity and tolerability of MTL-CEBPA as a single agent was observed, provides an excellent foundation on which to advance MTL‑CEBPA in combination with other cancer therapies and serves as a strong, general validation of our novel approach to targeting cancer," said Robert Habib, CEO of MiNA Therapeutics. "In addition to the ongoing evaluation of MTL-CEBPA in combination with sorafenib in patients with advanced liver cancer, the new pre-clinical findings support investigating MTL‑CEBPA and anti-PD1 checkpoint combination therapy in patients with other solid tumour cancers."

Final results of the first-in-human evaluation of MTL-CEBPA as a single agent demonstrated MTL-CEBPA to be well tolerated at all dose levels with clear pharmacological activity. In the study, MTL-CEBPA was evaluated as a single agent in 39 patients with advanced liver cancer and liver disease across escalating dose levels and dose frequencies in which no maximum tolerated dose was identified. Pharmacological activity was observed in patients with significant activation of CEBPA target gene and subsequent changes in white blood cell count. Analysis of paired biopsies indicated repopulation of the tumour microenvironment from immuno-suppressive to mature myeloid cells. In 35 patients evaluable for efficacy, partial tumour response was achieved in 1 patient, and stable disease was achieved in 15 patients. Following discontinuation of MTL‑CEBPA, 8 patients received subsequent tyrosine kinase inhibitor therapy. Of 5 patients treated with sorafenib, 4 experienced durable, objective tumour responses including 3 complete tumour responses durable for over 1 year. The ongoing OUTREACH Phase 1b study continues to evaluate MTL-CEBPA in combination with sorafenib standard of care.

Separately, a new pre-clinical study described the synergistic benefits of combining MTL‑CEBPA with anti-PD1 checkpoint inhibition in an immunocompetent mouse model of colon cancer. Compared to single agent treatments, the combination treatment resulted in synergistic improvements in tumour growth inhibition. Synergistic increases in infiltration of cytotoxic T lymphocytes (TILs) evidenced the immunological role of MTL-CEBPA in the tumour microenvironment.

The posters will be made available on the Company’s website in the Publications section under "RNA Activation".

Presentation information

Title: First-in-human, first-in-class phase I study of MTL-CEBPA, a RNA oligonucleotide targeting the myeloid cell master regulator C/EBP-α, in patients with advanced hepatocellular cancer
Poster no: 455PD (Abstract 2878)
Session: Poster Discussion – Developmental therapeutics
Date / time: 16:30 – 18:00 CET, Saturday 28 September 2019
Location: Alicante Auditorium (Hall 3)

Title: Targeting myeloid-derived suppressor cells and T cells: combination treatment with MTL-CEBPA and PD-1 antibody in a mouse syngeneic CT26 model
Poster no: 1230P (Abstract 3089)
Session: Poster Display Session 3, Immunotherapy of cancer
Date / time: 12:00 – 13:00 CET, Monday 30 September 2019
Location: Poster Area (Hall 4)

About MTL-CEBPA
MTL-CEBPA is the first therapy to specifically up-regulate CCAAT/enhancer binding protein alpha (C/EBP-α), a transcription factor that acts as a master regulator of myeloid cell lineage determination and differentiation. Dysregulated myeloid cells have been implicated in several diseases and identified as a critical barrier for many therapies to induce clinical responses in solid tumour cancers. In pre-clinical studies MTL-CEBPA has been shown to improve the anti-tumour activity of cancer therapies by targeting dysregulated myeloid cells and reducing their suppression in the tumour microenvironment.

On September 30, 2019 Iksuda Therapeutics (Iksuda), a developer of next generation Antibody Drug Conjugates (ADCs), reported the first data on its lead ADC, IKS01. IKS01, an ADC targeting the folate receptor, has shown significant anti-tumour efficacy in pre-clinical models of ovarian and lung tumours, each of which included a broad range of folate-receptor alpha (FRA) expression (Press release, Iksuda Therapeutics, SEP 30, 2019, View Source [SID1234539947]). The data is currently being presented at ESMO (Free ESMO Whitepaper) Congress 2019 in Barcelona, Spain.

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ADCs allow for the targeted delivery of a potent cytotoxic payload to tumours, resulting in selective killing with increased efficacy and less off-target toxicity than standard-of-care chemotherapies. Frequent over-expression of FRA in ovarian and non-small-cell lung cancer (accounting for 80% of lung cancer cases) and relative lack of expression in normal tissue, make it an attractive therapeutic target. However, anti-tumour activity is generally limited to patients whose tumours express high levels of FRA.

IKS01 is an ADC comprised of an FRA-targeting antibody conjugated via Iksuda’s PermaLink technology to Femtogenix’s highly potent FGX2-62 payload. IKS01 is target specific and these new data confirm that it is highly effective in causing tumour regression in FRA-expressing models at doses that are well-tolerated, significantly more active than a benchmark ADC and caused complete regressions in low/moderate FRA-expressing models.

The IKS01 data is a major advancement of Iksuda’s ADC drug pipeline, from which it aims to progress multiple candidates towards first clinical studies in 2020.

Dave Simpson PhD, Chief Executive Officer, Iksuda Therapeutics, said: "Ovarian cancer is one of the most deadly gynaecological cancers and lung cancer remains a leading cause of cancer-related death. The IKS01 data highlight the potential impact of our ADC pipeline by targeting difficult-to-treat tumours and advancing current standard of care."

Iksuda Therapeutics’ will be exhibiting its poster: ‘IKS01, a next generation antibody drug conjugate (ADC) designed to be efficacious in tumors with low and moderate levels of folate receptor alpha (FRA) expression’ until 1st October at ESMO (Free ESMO Whitepaper) Congress 2019, presentation number 58P.

On September 30, 2019 IMV Inc. (Nasdaq: IMV; TSX: IMV), a clinical stage immuno-oncology company, reported preliminary results from its ongoing Phase 2 basket trial, evaluating DPX-Survivac in combination with Merck’s Keytruda (pembrolizumab) and intermittent low dose cyclophosphamide (CPA) in patients with advanced and metastatic solid tumors (Press release, IMV, SEP 30, 2019, View Source [SID1234539946]). The data were presented during the Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) poster session at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2019 Congress, being held September 27 – October 1, 2019, in Barcelona, Spain.

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"We are encouraged by the initial response observed from these preliminary data, which feature a safety profile consistent with observations across other studies of DPX-Survivac as well as promising signs of clinical activity. Importantly, these results expand our clinical dataset into four additional hard-to-treat solid tumor indications, as we continue to explore the broad potential of our targeted T cell therapy in more than 20 solid and hematological tumor types that express survivin," said Frederic Ors, IMV’s Chief Executive Officer. "Later this year, we anticipate additional data from ongoing studies of DPX-Survivac in our lead indications – including topline results from DeCidE1, a Phase 2 study evaluating DPX-Survivac in ovarian cancer, and updated results from SPiRel, a Phase 2 study evaluating DPX-Survivac in combination with Keytruda in r/r DLBCL – both of which have demonstrated this program’s potential to safely generate a durable clinical response."

Preliminary Results from the Phase 2 Basket Trial

At the time of cut-off, 23 patients were enrolled across all five patient cohorts. This includes 19 patients across all cohorts who received DPX-Survivac in combination with pembrolizumab with CPA, and four patients from the ovarian cancer cohort receiving DPX-Survivac with only pembrolizumab:

Preliminary results from the first on-study scan showed tumor reduction in patients with ovarian cancer (with and without CPA), non-small cell lung cancer (NSCLC) and bladder cancer;
Partial responses observed at first scan in two subjects (bladder cancer, ovarian cancer); 19/23 subjects are still active on study treatment.
T cell infiltration observed in biopsy samples from subjects who achieved tumor reduction on treatment;
Eight ovarian cancer patients were enrolled in the study, randomized 1:1 to treatment with and without CPA. Tumor control and tumor reductions were observed in both groups; and
Safety evaluation on all evaluable patients demonstrated that treatment was well-tolerated, with no related Grade 3-4 or immune-related adverse events (AEs) reported.
The poster is available on the Investors section of the company’s website, under "Events, Webcasts & Presentations" at www.imv-inc.com.

About the Phase 2 Basket Trial

IMV’s Phase 2 basket trial is an open label, multi-center study, evaluating DPX-Survivac across five cohorts of patients with bladder cancer, liver cancer (hepatocellular carcinoma), ovarian cancer (with and without CPA), NSCLC and tumors shown to be positive for the microsatellite instability high (MSI-H) biomarker.

Subjects will receive DPX-Survivac (SC: 2 x 0.25 mL every three weeks, followed by up to 11 x 0.1 mL every nine weeks), in combination with pembrolizumab (IV: 200 mg every 3 weeks cycle) and CPA (oral: 50 mg BID on alternating weeks) across five cohorts of patients with bladder cancer, liver cancer (hepatocellular carcinoma), ovarian cancer, NSCLC and tumors shown to be positive for the microsatellite instability high (MSI-H) biomarker. The study is designed to assess primary endpoints of safety and objective response rate (ORR), with multiple secondary and exploratory measures.

The study included a safety lead-in, which included 20 patients from all five cohorts. The five cohorts are now expanded to recruit additional subjects following a Simon two stage design. Enrollment in the ovarian cancer cohort will be randomized 1:1 into two arms with and without CPA. All other cohorts will utilize a single-arm design and administer treatment with the triple combination. As of Sept. 27th, 2019, 28 patients are enrolled (50 were screened). IMV expects to enroll 184 patients across clinical sites in the U.S. and Canada.

About DPX-Survivac

DPX-Survivac is the lead candidate in IMV’s new class of immunotherapies that programs targeted T cells in vivo. It has demonstrated the potential for industry-leading targeted, persistent, and durable T cell activation. IMV believes this mechanism of action (MOA) is key to generating durable solid tumor regressions. DPX-Survivac consists of survivin-based peptides formulated in IMV’s proprietary DPX drug delivery platform. DPX-Survivac is designed to work by eliciting a cytotoxic T cell immune response against cancer cells presenting survivin peptides on their surface.

Survivin, recognized by the National Cancer Institute (NCI) as a promising tumor-associated antigen, is broadly over-expressed in most cancer types, and plays an essential role in antagonizing cell death, supporting tumor-associated angiogenesis, and promoting resistance to chemotheratherapies. IMV has identified over 20 cancer indications in which survivin can be targeted by DPX-Survivac.

DPX-Survivac has received Fast Track designation from the U.S. Food and Drug Administration (FDA) as maintenance therapy in advanced ovarian cancer, as well as orphan drug designation status from the U.S. FDA and the European Medicines Agency (EMA) in the ovarian cancer indication.

On September 30, 2019 X4 Pharmaceuticals, Inc. (Nasdaq: XFOR), a clinical-stage biopharmaceutical company focused on the development of novel therapeutics for the treatment of rare diseases, reported positive results from the Phase 2a portion of its open-label Phase 1/2 clinical trial of mavorixafor (X4P-001) in combination with axitinib (Inlyta) in patients with advanced clear cell renal cell carcinoma (ccRCC) (Press release, X4 Pharmaceuticals, SEP 30, 2019, View Source [SID1234539945]). Data were presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2019 Congress today in Barcelona.

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Combination therapy with mavorixafor and approved tyrosine kinase inhibitor (TKI) axitinib was generally well tolerated with a manageable safety profile and demonstrated clinical improvement with encouraging median progression free survival (mPFS) in a heavily pretreated advanced ccRCC patient population. Of the 65 patients in the trial, 49 patients (or 75%) received mavorixafor + axitinib as a third- to ninth-line therapy, having received between two and eight prior therapies with a TKI, immuno-oncology (IO) agent, or other systemic therapy. Fifty-seven of the 65 patients in the trial (or 88%) had an intermediate or poor prognosis.

Overall mPFS across clinically evaluable patients receiving mavorixafor + axitinib (n=62) was 7.4 months. Predefined subpopulations examined patients with immediate prior TKI and IO treatment. Patients treated in the subgroup with immediate prior TKI therapy (n=34) demonstrated an objective response rate (ORR) of 18% and an increased mPFS of 7.4 months. This is a greater than 50% improvement from the 4.8-month historical mPFS with axitinib alone.1 Patients treated with mavorixafor + axitinib in the subgroup with immediate prior IO therapy (n=18) had an ORR of 61% and an increased mPFS of 11.6 months. In addition, eight of the 65 patients remain on the combination therapy today, with durations of treatment of 17 months or longer. Results suggest mavorixafor may enhance clinical response to axitinib and other TKIs that target tumor angiogenesis, as well as immunotherapy agents.

"In recent years a growing number of vascular endothelial growth factor (VEGF) TKI-based therapies (e.g., axitinib + pembrolizumab), have improved outcomes for patients with ccRCC. Despite these advances, most patients eventually develop resistance to therapy, and new treatment options are necessary to meet this unmet medical need," commented David F. McDermott, M.D., Beth Israel Deaconess Medical Center, Harvard Medical School and lead investigator of the study. "In this trial of mavorixafor, a novel CXCR4 pathway inhibitor, and axitinib in patients with metastatic ccRCC who had failed prior therapy, the combination was well tolerated and the anti-tumor activity was encouraging. We look forward to confirming the efficacy of mavorixafor in a randomized trial."

This Phase 1/2, multi-center, open-label trial of mavorixafor in combination with axitinib included 65 patients with histologically confirmed advanced ccRCC, all of whom received at least one prior systemic therapy. The safety analyses included 65 patients from Phases 1/2 who were treated with 400 mg mavorixafor (200 mg twice daily or 400 mg once daily) + 5 mg axitinib twice daily. Treatment responses were assessed using Response Evaluation Criteria in Solid Tumor, or RECIST v1.1 (a validated set of criteria to assess changes in tumor burden), every eight weeks from day one for 80 weeks, and then every 12 weeks thereafter, by blinded, independent central review. Treatment-related serious adverse events were diarrhea, hyperkalemia and hypertension (n=2, or 3%) and blood creatinine increased, dehydration, fatigue, hepatic enzyme increase, nausea, sepsis, trachea-oesophageal fistula, and vomiting (n=1 each, or 1.5%).

"These promising results, especially among heavily pre-treated patients with poor prognoses, add to a published body of evidence supporting mavorixafor’s generally favorable safety and tolerability profile and its novel CXCR4 mechanism of action that has been shown to induce immune-mediated antitumor activity as a single agent and in combination with approved therapies," said Lynne Kelley, M.D., FACS, Chief Medical Officer of X4 Pharmaceuticals. "We are encouraged by these data, including the eight patients who remain on combination therapy with mavorixafor and axitinib for 17 months or longer. We look forward to continuing to explore the potential benefit of mavorixafor in underserved cancer patients with solid tumors, including as a potential triple combination agent in addition to TKI and checkpoint inhibitor therapies or in combination with other standard of care treatments."

Mavorixafor is a potentially first-in-class, once-daily, oral, small molecule antagonist of chemokine receptor CXCR4. CXCR4 signaling is thought to contribute to the lack or loss of tumor responsiveness to angiogenesis inhibitors, like axitinib. Elevated expression of CXCR4 by RCC tumors is also correlated with an overall poor prognosis. In xenograft models studied previously, mavorixafor in combination with axitinib, a VEGF receptor TKI, reduced myeloid-derived suppressor cell infiltration and proangiogenic signals, and demonstrated greater than additive antitumor activity.

Details of the investor conference call and webcast are as follows:
Time and Date: Monday, September 30 at 8:00 AM EDT / 2:00 PM CEST
US Toll-Free Dial-In Number: (866) 721-7655
International Dial-In Number: (409) 216-0009 / Spain 0934923253
Conference ID: 4787329
Webcast: A live audio webcast of the conference call may be accessed in the "Investors" section of the Company’s website at the following link: View Source

About Mavorixafor

X4 Pharmaceuticals’ lead product candidate, mavorixafor (X4P-001), is a potentially first-in-class, once-daily, oral inhibitor of CXCR4, currently in Phase 2 development for the treatment of clear cell renal cell carcinoma (ccRCC). Mavorixafor has demonstrated single and combination agent activity and proof of mechanism in Phase 1b and Phase 2a trials, respectively, along with a favorable safety and tolerability profile. Mavorixafor is also in development for the treatment of WHIM syndrome, as well as Severe Congenital Neutropenia (SCN) and Waldenström’s macroglobulinemia (WM). Mavorixafor was designated orphan drug status by the U.S. Food and Drug Administration in 2018 and by the European Commission in 2019 for the treatment of WHIM syndrome.