On April 3, 2019 Iovance Biotherapeutics, Inc. (NASDAQ: IOVA), a late-stage biotechnology company developing novel cancer immunotherapies based on tumor-infiltrating lymphocyte (TIL) technology, reported an update to its clinical programs with TIL therapy in the treatment of cervical cancer and non-small cell lung cancer (NSCLC) (Press release, Iovance Biotherapeutics, APR 3, 2019, View Source;p=RssLanding&cat=news&id=2393311 [SID1234534993]). The protocol for innovaTIL-04 (C-145-04), the Phase 2 study in cervical cancer, was amended to increase the sample size to 59 and to modify the primary endpoint of Objective Response Rate (ORR) to be determined by a Blinded Independent Review Committee (BIRC). The company made the changes in anticipation of a meeting with the U.S. Food and Drug Administration (FDA) planned for later this year to discuss the registration pathway for LN-145 in cervical cancer. Earlier this year, LN-145 received a Fast Track designation for cervical cancer.

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"Based on the prior FDA interactions on lifileucel for melanoma, we amended the protocol for the ongoing Phase 2 study of LN-145 in cervical cancer to incorporate certain design elements that we believe are necessary for registration," commented Maria Fardis, Ph.D., president and chief executive officer of Iovance Biotherapeutics. "We believe these amendments will help to facilitate the discussion of the registration requirements necessary for this unmet medical need. We look forward to providing an update on the registrational path for LN-145 in cervical cancer later this year."

In addition to the modifications to the cervical study, the company will close the IOV-LUN-201 study in NSCLC and instead plans to add an additional arm to the global IOV-COM-202 study. The new arm will allow for treatment of PD-1/PD-L1 naive NSCLC patients with combination of LN-145 and pembrolizumab. The company anticipates that some of the clinical sites from the IOV-LUN-201 study will be added to the IOV-COM-202 study.

"As the treatment landscape evolves in non-small cell lung cancer, Iovance is adapting its clinical development plan to address the current medical needs," added Dr. Fardis. "Iovance continues to be committed in offering TIL therapy for both early and late line NSCLC through the IOV-COM-202 protocol."

Details on the updates include:

IOV-LUN-201. The Phase 2 trial combining LN-145 and durvalumab for the treatment of patients with non-small cell lung cancer (NSCLC) has been open for approximately a year (NCT 03419559). There are currently eight active sites in the United States seeking patients. No patients have been dosed to date. The treatment landscape for NSCLC has evolved rapidly in the past year. Combination treatment with the PD-1 inhibitor pembrolizumab, with or without chemotherapy, is now approved for use in a first-line setting for metastatic NSCLC and is now standard of care for these patients. Given the advances in the standard of care for these patients, Iovance and AstraZeneca have decided to close the IOV-LUN-201 study.

IOV-COM-202. Iovance remains highly committed to development of LN-145 in NSCLC. The company plans to add some of the existing NSCLC clinical sites and investigators into the IOV-COM-202 trial. IOV-COM-202 is a global study with sites participating from the United States and Europe. As the patient population is expected to be more accessible outside of the United States, this is believed to be a more appropriate location for recruitment of PD-1/PD-L1 naive NSCLC patients.

On April 3, 2019 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) reported its data from its poster presentation at the AACR (Free AACR Whitepaper) or American Association of Cancer Research annual Meeting 2019 demonstrating that the targeted radiation delivered by Actimab-A to CD33 expressing cells can deplete MCL-1 levels in tumor cells, thereby removing a mechanism of resistance and rendering them more susceptible to venetoclax (Press release, Actinium Pharmaceuticals, APR 3, 2019, View Source [SID1234534939]). Further, the induction of direct AML cell death via double-stranded DNA breaks by Actimab-A provides a second mechanism for enhancing synergistic potency with venetoclax. Actimab-A is an ARC or Antibody Radiation Conjugate comprised of the anti-CD33 monoclonal antibody lintuzumab and the potent alpha-particle emitting radioisotope Ac-225 or Actinium-225. Venetoclax is a BCL-2 or B-Cell Lymphoma 2 inhibitor that is jointly developed and marketed by AbbVie and Genentech and is approved for patients with AML or Acute Myeloid Leukemia, Chronic Lymphocytic Leukemia, and Small Lymphocytic Leukemia. The poster can be viewed on Actinium’s website here.

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Highlight’s of Actinium’s poster presentation are as follows:

Actimab-A treatment of venetoclax resistant AML cells led to a decrease in MCL-1 levels. MCL-1 is a protein in the BCL-2 family of anti-apoptotic proteins, which is overexpressed in relapsed or refractory AML cells and has been shown to mediate resistance to venetoclax.
The same Actimab-A treatment reduced BCL-XL. BCL-XL is another protein in the BCL-2 family and also been proposed to mediate resistance to venetoclax.
Additional studies demonstrated that Actimab-A produced double-stranded DNA breaks in two cell lines resistance to venetoclax.
At all dose levels and time points, Actimab-A significantly increased double-stranded DNA breaks compared to cells treated with lintuzumab alone.
In a venetoclax resistant AML in vivo tumor model, statistically significant reduction in tumor size was observed in animals receiving the combination of Actimab-A and venetoclax compared to venetoclax alone.
At evaluation on day 38, complete responses were reported in 3 of 5 animals receiving the combination of Actimab-A and venetoclax while no animals receiving venetoclax alone achieved a complete response at any time point.
100% survival at day 40 was observed in cohorts receiving Actimab-A and venetoclax while no animals treated with venetoclax alone survived beyond day 30.
Dr. Dale Ludwig, Actinium’s Chief Scientific Officer, said, "The results of these studies further our enthusiasm for the combination of Actimab-A and venetoclax. Expanding on our previous in vitro work, it is validating to observe multiple synergies derived from Actimab-A’s unique targeted radiation mechanism of action including MCL-1 reduction. Given the role this protein plays in AML cell resistance to venetoclax, it is exciting to see its depletion with Actimab-A, resulting in increased cell death and tumor control in these studies. We are also excited to demonstrate that Actimab-A causes double-stranded DNA breaks for which there is no known resistance or repair mechanism. It is important to note that these findings were observed in cell lines and xenograft animal models based on venetoclax resistant cell lines. These data further support the advancement of the combination of Actimab-A and Venetoclax into clinical trials as we are doing with two distinct clinical trials."

Actinium has filed a patent on the combination of a targeted alpha-emitting therapeutic such as Actimab-A together with a BCL-2 inhibitor, which includes venetoclax, as a method to treat cancer. Actinium has initiated a Phase 1/2 trial that is studying Actimab-A in combination with venetoclax for patients with relapsed or refractory AML and is planning a Phase 1/2 trial that will study Actimab-A and venetoclax with a hypomethylating agent also for patients with relapsed or refractory AML, which is expected to be initiated in the first half of 2019.

Sandesh Seth, Actinium’s Chairman and CEO, said, "As we advance towards the clinic with our second Actimab-A venetoclax combination trial, it is encouraging to see multiple synergies in robust pre-clinical models. With many patients not responding to or having limited duration of their responses with venetoclax treatment, these important findings together with our extensive clinical data with Actimab-A will be beneficial to the advancement of our two combination trials. This work also showcases Actinium’s integration of our research and development and clinical development efforts that can result in rapid translation to the clinic. With a robust intellectual property portfolio around our AWE technology platform, we see a multitude of opportunities to leverage targeted radiation via our ARC’s in combination with other therapeutic modalities to generate potential therapies for patients with high unmet medical needs that are underserved by current therapeutic approaches."

On April 3, 2019 AVEO Pharmaceuticals, Inc. (Nasdaq: AVEO) ("AVEO" or the "Company"), a biopharmaceutical company seeking to advance targeted medicines for oncology and other unmet medical needs, reported the pricing of its previously announced underwritten public offering of 21,739,131 shares of common stock and short-term warrants to purchase up to 21,739,131 shares of common stock at a price to the public of $1.15 per share and accompanying warrant (Press release, AVEO, APR 3, 2019, View Source [SID1234534975]). The Company expects to receive gross proceeds of approximately $25 million from the offering. The offering is expected to close on or about April 8, 2019, subject to customary closing conditions.

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H.C. Wainwright & Co. is acting as sole book-running manager for the offering.

Each warrant has an exercise price of $1.25 per share of common stock, will be immediately exercisable upon issuance, and will expire on the second anniversary of the date of issuance.

The Company has granted the underwriters a 30-day option to purchase up to 3,260,869 additional shares of common stock and/or warrants to purchase 3,260,869 shares of common stock at the public offering price, less underwriting discounts and commissions.

The Company intends to use the net proceeds from the offering for ongoing clinical and preclinical development of its product candidates, as well as for working capital and other general corporate purposes.

The securities described above were offered by the Company pursuant to a "shelf" registration statement on Form S-3 (File No. 333-221837) previously filed with and declared effective by the Securities and Exchange Commission ("SEC") on December 15, 2017. A preliminary prospectus supplement and an accompanying prospectus relating to the offering has been filed with the SEC and is available on the SEC’s website at www.sec.gov. A final prospectus supplement and accompanying prospectus will be filed with the SEC. Electronic copies of the final prospectus supplement and the accompanying prospectus relating to the offering may also be obtained, when available, from H.C. Wainwright & Co., LLC, 430 Park Avenue, 3rd Floor, New York, NY 10022, or by calling (646) 975-6996 or by emailing [email protected].

This press release shall not constitute an offer to sell or the solicitation of an offer to buy any of the Company’s securities, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

On April 3, 2019 Immunocore Limited, a leading T Cell Receptor (TCR) biotechnology company, reported that the U.S. Food and Drug Administration (FDA) has granted Fast Track Designation for its development program, the investigation of tebentafusp (IMCgp100) for the treatment of patients who are HLA-A*0201-positive with previously untreated, metastatic uveal melanoma (mUM) (Press release, Immunocore, APR 3, 2019, View Source [SID1234534958]).

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The pivotal study IMCgp100-202 is a 2:1 randomized study of tebentafusp compared with Investigator’s Choice (dacarbazine, ipilimumab or pembrolizumab) in HLA-A*0201 positive adult patients with previously untreated mUM. The primary endpoint is a comparison of overall survival.

"For patients with metastatic uveal melanoma, the prognosis is poor and has not meaningfully changed in decades. Our goal is to test whether tebentafusp can prolong survival for these patients." comments David Berman, Head of R&D of Immunocore. "We are delighted that tebentafusp has been granted Fast Track Designation."

The FDA’s Fast Track program is designed to facilitate the development, and expedite the review of drugs to treat serious conditions and fill an unmet medical need. A drug granted Fast Track Designation may be eligible for several benefits, including more frequent meetings and communications with the FDA and, if relevant criteria are met, the potential for Accelerated Approval, Priority Review or Rolling Review of a Biologics License Application (BLA) or New Drug Application (NDA).

Tebentafusp has previously been granted orphan drug designation for melanoma by the US FDA and Promising Innovative Medicine designation under UK Early Access to Medicines Scheme.

On April 3, 2019 Sierra Oncology, Inc. (Nasdaq: SRRA), a clinical stage drug development company focused on advancing targeted therapeutics for the treatment of patients with unmet needs in hematology and oncology, reported preclinical data for its novel oral Cdc7 inhibitor, SRA141, in a late-breaking poster being presented at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019 in Atlanta, Georgia (Press release, Sierra Oncology, APR 3, 2019, View Source [SID1234534995]).

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"Prior studies demonstrated that SRA141 potently and selectively inhibits Cdc7, resulting in robust anti-tumor efficacy in colorectal xenograft models, however, the compound’s exact mechanism of action has not been characterized previously. Our findings reveal a potentially novel mechanism of cytotoxicity for Cdc7 inhibitors that is distinct from other agents, and thus SRA141 may herald a new class of cancer therapeutic agents with a differentiated anti-tumor profile," said Dr. Eric J. Brown, Associate Professor of Cancer Biology at the Perelman School of Medicine of the University of Pennsylvania, and member of Sierra’s DNA damage response (DDR) Advisory Committee.

"SRA141 does not induce G1 cell cycle arrest or replication stress, thereby distinguishing it from other agents such as palbociclib or SRA737. Rather, SRA141 alters DNA replication dynamics and delays cell cycle progression, ultimately resulting in caspase-dependent cell death associated with mitotic accumulation. Promisingly, we believe we have shown for the first time that this mechanism appears to synergize with anti-apoptotic drugs, such as venetoclax, and dysregulators of mitosis, such as barasertib. This differentiated mechanism of action supports a potentially unique spectrum of clinical opportunities for SRA141 as both monotherapy and in combination with pro-apoptotic and mitotic disrupting agents," said Dr. Christian Hassig, Chief Scientific Officer, Sierra Oncology.

SRA141 AACR (Free AACR Whitepaper) Late-Breaking Poster:
Date/Time: Wednesday, April 3rd from 8:00 am to 12:00 pm ET
Session: Late-Breaking Research: Molecular and Cellular Biology / Genetics 2
Title: CDC7 kinase inhibition by SRA141 induces a potentially novel caspase-dependent tumor cell apoptosis associated with altered DNA replication and cell cycle dynamics.
Authors: Veena Jagannathan, Snezana Milutinovic, Ryan J. Hansen, Bryan Strouse, Christian Hassig and Eric J. Brown.
Location: Georgia World Congress Center, Exhibit Hall B, Poster Section 41, Poster #5

The poster will be made available on the company’s website at www.sierraoncology.com.

About SRA141 targeting Cdc7
SRA141 is a novel, potent, orally bioavailable selective inhibitor of Cell division cycle 7 (Cdc7) kinase. Owing to its important role in DNA replication, and its overexpression in various neoplasms, Cdc7 is an attractive therapeutic target with emerging clinical validation in oncology.

Cdc7, together with its partner proteins Dbf4 or Drf1, is responsible for activating DNA replication origin firing during S-phase through phosphorylation and activation of the MCM2-7 helicase. Cdc7 also has functions within the DNA Damage Response (DDR) and mitosis. Over-expression of Cdc7 and its partner proteins is correlated with unfavorable clinical outcomes and poor survival in a broad range of solid tumors and hematological malignancies.

SRA141 has been shown to cause cancer cell death in a p53-independent manner and to induce tumor regression or stasis in a variety of in vivo cancer models, including complete and partial regressions in animal models of colorectal cancer.

An Investigational New Drug Application (IND) filing has been accepted by the U.S. Food and Drug Administration (FDA) for SRA141, and Sierra Oncology has prepared for a potential Phase 1/2 trial of the drug candidate in patients with advanced colorectal cancer. Sierra Oncology is currently evaluating the optimal timing to commence this trial within the context of its recently expanded portfolio.

Sierra Oncology retains the global commercialization rights to SRA141