On April 12, 2021 Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, reported the presentation of three posters at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2021 Annual Meeting being held virtually from April 10-15, 2021 .

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"These data highlight the significant potential of our advanced and differentiated ROR1 platform, where cirmtuzumab has demonstrated promising preclinical and clinical activity across a broad spectrum of cancer indications. The results from the current preclinical studies create additional optionality to pursue future indications, which we are actively evaluating while we advance our Phase 2 cirmtuzumab program in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) and advance our earlier-stage CAR-T and CAR-NK cell programs that also target ROR1," said James Breitmeyer, M.D., Ph.D., Oncternal’s President and CEO.

Poster Presentations:

Session Date and Time: April 10, 2021 8:30 AM – 11:59 PM ET
Session Title: Stem Cell Biology
Poster Title: A Phase 1b Trial of Cirmtuzumab and Paclitaxel in Locally Advanced/Unresectable or Metastatic Her2 Negative Breast Cancer (Poster #LB255)
- In this Phase 1b investigator-initiated clinical trial from the University of California San Diego (UC San Diego) School of Medicine, 15 patients were treated with cirmtuzumab and paclitaxel after receiving a median of six prior therapies for metastatic disease. Of 15 intent-to-treat patients as of April 10, 2021, eight patients (53%) had a best response of partial response (PR), one of which remained durable for 52 weeks, and four patients (27%) had stable disease (SD). Of the 14 patients who were evaluable for efficacy per protocol, eight patients (57%) had a PR and four patients (29%) had SD. All reported adverse events were related to paclitaxel except for one Grade 3 neutropenia that was categorized as possibly related to cirmtuzumab. No patient stopped cirmtuzumab due to toxicity, no dose reductions of cirmtuzumab were required and no dose limiting toxicities were observed. The authors concluded that as of the cutoff date, cirmtuzumab given with paclitaxel was well-tolerated and demonstrated no added toxicity over what was expected with paclitaxel alone in heavily pre-treated patients with metastatic breast cancer. As of the cutoff date, all pre-treatment breast cancer samples available for analysis expressed ROR1 as assessed by immunohistochemistry. The authors concluded that further clinical evaluation of cirmtuzumab was warranted in patients with breast cancer.
Poster Title: Inhibition of ovarian and endometrial cancer cell proliferation by an anti-ROR1 monoclonal antibody (Poster #1062)
Session Title: Combination Therapies
Session Date and Time: April 10, 2021 8:30 AM – 11:59 PM ET
In this preclinical study from the University of New South Wales, high-grade serous ovarian cancer (HGSOC) and endometrial cancer cell lines were treated with cirmtuzumab alone or in combination with chemotherapeutic agents, cisplatin, paclitaxel, or the PARP inhibitor olaparib. The authors concluded that cirmtuzumab demonstrated single agent activity against these tumor types, and also enhanced the anti-proliferative effects of commonly-used chemotherapies in these cancers. Future studies will further evaluate cirmtuzumab in ovarian and endometrial cancers in vitro and in relevant in vivo models.
Poster Title: Selective androgen receptor degraders for the treatment of androgen receptor-positive, triple-negative breast cancer (Poster # 1235)
Session Title: Novel Antitumor Agents
Session Date and Time: April 10, 2021 8:30 AM – 11:59 PM ET
In this preclinical study from the University of Tennessee, androgen receptor (AR)-positive triple negative breast cancer (TNBC) cell proliferation and tumor growth were inhibited using Oncternal’s investigational selective androgen receptor degraders (SARDs). Notably, the SARDs demonstrated anti-tumor activity in a TNBC patient-derived xenograft model expressing a splice variant of the AR. Oncternal believes that these results support further development of Oncternal’s SARDs as a potential treatment for women affected by the luminal androgen receptor (LAR) subtype of TNBC.
About Cirmtuzumab
Cirmtuzumab is an investigational, potentially first-in-class monoclonal antibody targeting ROR1, or Receptor tyrosine kinase-like Orphan Receptor 1. Cirmtuzumab is currently being evaluated in a Phase 1/2 clinical trial in combination with ibrutinib for the treatment of MCL or CLL, in a collaboration with the University of California San Diego (UC San Diego) School of Medicine and the California Institute for Regenerative Medicine (CIRM). In addition, Oncternal is supporting two investigator-sponsored studies being conducted at the UC San Diego School of Medicine: (i) a Phase 1b clinical trial of cirmtuzumab in combination with paclitaxel for the treatment of women with HER2-negative metastatic or locally advanced, unresectable breast cancer, and (ii) a Phase 2 clinical trial of cirmtuzumab in combination with venetoclax, a Bcl-2 inhibitor, in patients with relapsed/refractory CLL.

ROR1 is a potentially attractive target for cancer therapy because it is an onco-embryonic antigen – not usually expressed on adult cells, and its expression confers a survival and fitness advantage when reactivated and expressed by tumor cells. Researchers at the UC San Diego School of Medicine discovered that targeting a critical epitope on ROR1 was key to specifically targeting ROR1 expressing tumors. This led to the development of cirmtuzumab, that binds this critical epitope of ROR1, which is highly expressed on many different cancers but not on normal tissues. Preclinical data showed that when cirmtuzumab bound to ROR1, it blocked Wnt5a signaling, inhibited tumor cell proliferation, migration and survival, and induced differentiation of the tumor cells. The FDA has granted Orphan Drug Designations to cirmtuzumab for the treatment of MCL and CLL/small lymphocytic lymphoma. Cirmtuzumab is in clinical development and has not been approved by the FDA for any indication.

About SARDs
Oncternal’s preclinical Selective Androgen Receptor Degrader (SARD) program is based on inventions by Professors Duane Miller and Ramesh Narayanan from the University of Tennessee Health Science Center (UTHSC) in Memphis, TN. The androgen receptor (AR) is a validated target for the treatment of castration-resistant prostate cancer (CRPC) and there are currently several FDA-approved AR-targeting therapies. However, resistance development occurs, often through mutations or AR splice variants rendering most therapies ineffective. In preclinical studies, Oncternal’s investigational SARDs have demonstrated activity against prostate cancer tumors resistant to approved AR-targeting therapies. Oncternal is currently evaluating strategic development options for SARDs as potential therapies for castration-resistant prostate cancer (CRPC) and LAR-TNBC as well as AR-driven non-oncology indications.

On April 12, 2021 Greenwich LifeSciences, Inc. (Nasdaq: GLSI) (the "Company"), a clinical-stage biopharmaceutical company focused on the development of GP2, an immunotherapy to prevent breast cancer recurrences in patients who have previously undergone surgery, reported a poster of the final 5 year GP2 Phase IIb clinical trial immune response data on April 10th at the 2021 AACR (Free AACR Whitepaper) Annual Meeting (Press release, Greenwich LifeSciences, APR 12, 2021, View Source [SID1234577894]). Immune response is the primary mechanism of action for GP2 and is critical to developing dosing and booster treatment strategies that are designed to achieve and sustain peak immunity, as well as to prevent metastatic breast cancer recurrences.

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It has been previously reported that the completion of the GP2+GM-CSF Primary Immunization Series (PIS) reduced recurrence rates to 0% over a 5 year follow-up period in HER2 3+ patients who had received a standard course of trastuzumab after surgery. The abstract and poster present the final immune response results over the 5 year follow-up period, assessing peak immunity compared to baseline and between patients treated with GP2+GM-CSF versus GM-CSF alone, including by HER2 status.

Summary of the Final 5 Year Immune Response Data as Previously Presented:

Potent immune response data supports the previously reported clinical outcome of 0% metastatic breast cancer recurrences over 5 years of follow up, if a patient completes the Primary Immunization Series over the first 6 months of GP2 treatment.
Statistically significant peak immunity was reached after 6 months of GP2 treatment as measured in both the Dimer Binding Assay and the DTH skin test.
HER2 3+ population immune response was similar to the HER2 1-2+ population immune response, suggesting the potential to treat the HER2 1-2+ population (including triple negative breast cancer) with GP2 immunotherapy in combination with trastuzumab (Herceptin) based products and other clinically active agents.
Broad based immune response suggests that GP2 immunotherapy and Herceptin based products may also have the potential to treat other HER2 1-3+ expressing cancers.
Dr. Thompson commented, "The analysis of the immune response data in the Phase IIb trial provides mechanistic confirmation of treatment effect correlated with the clinical response previously reported. GP2 treated patients, independent of their HER2 status, experienced a potent immune response to GP2, far greater than patients treated with placebo. In addition, this data has provided us with insight that will guide the upcoming Phase III trial. We believe that monitoring immune response will be an important aspect of the Phase III trial."

Excerpts from the AACR (Free AACR Whitepaper) Poster CT183:

Title: Final five year median follow-up data from a prospective, randomized, placebo-controlled, single-blinded, multicenter, phase IIb study evaluating a time series of immune responses using HER2/neu peptide GP2 + GM-CSF vs. GM-CSF alone after adjuvant trastuzumab in HER2 positive women with operable breast cancer

Each GP2 treated patient was scheduled to receive 6 intradermal injections with GP2+GM-CSF over the first 6 months of treatment as part of the Primary Immunization Series and 4 boosters every 6 months thereafter. Placebo patients received intradermal injections with GM-CSF alone.

Immune responses to GP2 were measured over time using a CD8 T cell dimer binding assay (Dimer Binding Assay) and delayed-type-hypersensitivity (DTH) skin tests. The Dimer Binding Assay detects the percentage of GP2 specific killer T cells that can kill recurring cancer cells. The DTH skin test measures the diameter of the skin immune response to GP2 in millimeters 48-72 hours after injection of GP2 without GM-CSF.

Figure 1 of the poster shows that GP2 immunity peaked at 6 months in HER2 3+ patients after they completed their first 6 immunizations, as measured by the Dimer Binding Assay. The data also shows that for the 2.5 years that the immune response was measured, the immunity was sustained and remained above baseline, resulting in 100% disease free survival (0% recurrence rate) over 5 years. In the placebo arm, the immune response was not as robust, resulting in 89% disease free survival (11% recurrence rate). Immune response in GP2-treated patients increased quickly during the Primary Immunization Series and remained statistically significantly above baseline for 6 months after the completion of the Primary Immunization Series. Some patients received boosters beginning at 12 months and the immune response was assessed one month after the receiving the booster.

Dimer Binding Assay: The Dimer Binding Assay detects the percentage of GP2 specific killer T cells that can kill recurring cancer cells. Ex vivo immune response was assessed over 2.5 years with blood draws at baseline, then after the 3rd and 6th immunizations in the Primary Immunization Series, and then after each booster. Immune responses were assessed by phenotypic clonal expansion assays in the majority of patients (n=113). GP2-specific CTLs were quantified in patients treated with GP2 using the Ig:A2 Dimer Assay and demonstrated an expansion over time, showing an increase over baseline after the 3rd immunization and remaining elevated for the entire course of follow-up.

Figure 2 of the poster shows the same Dimer Binding Assay data for HER2 3+ patients as in Figure 1, where the GP2 treated patients showed statistically significant dimer readings versus baseline (pre-vaccination) at 3, 6, and 12-13 months.

DTH Skin Test: The DTH skin test measures the diameter of the skin immune response to GP2 in millimeters, 48-72 hours after intradermal injection of GP2 without GM-CSF. A DTH reaction was used to assess in vivo immune responses in patients (n=150). The DTH orthogonal mean of the skin wheal was measured 48-72 hours after injection using the sensitive ballpoint-pen method and is compared using a Wilcoxon Rank-Sum. For GP2 treated patients, there was a significant increase in DTH reactions after the PIS compared to baseline DTH reactions.

Figure 3A shows that after completion of the 6th immunization after 6 months, GP2 treated patients showed a robust immune response using the DTH skin test, while the placebo did not (p = 0.009). Within GP2 treated patients, the change from baseline after 6 months was a median of 4.8 mm (mean of 11.6 mm), which was a statistically significant increase over baseline (p < 0.0001). The change from baseline in DTH at 6 months was more robust in the GP2 treated patients. Those patients had an 11.6 mm mean increase in DTH after 6 months of exposure while patients treated with GM-CSF alone had a 5.2 mm mean increase (p = 0.023). This DTH data supports the Dimer Binding Assay data that shows a peak immune response after 6 months.

Figure 3B shows that the DTH immune response for GP2 treated patients was similarly robust in HER2 3+ patients and HER2 1-2+ patients, independent of prior trastuzumab treatment and HER2 expression levels. Thus, GP2’s robust immune response in the HER2 1-2+ population suggests the potential to apply GP2 immunotherapy to HER2 low to intermediate expressing breast cancers, as well as to other HER2 1-3+ expressing cancers.

AACR Abstract CT183:

Title: Final five year median follow-up data from a prospective, randomized, placebo-controlled, single-blinded, multicenter, phase IIb study evaluating a time series of immune responses using HER2/neu peptide GP2 + GM-CSF vs. GM-CSF alone after adjuvant trastuzumab in HER2 positive women with operable breast cancer

Snehal S Patel, David B McWilliams, Mira S Patel, Christine T Fischette, Jaye Thompson and F Joseph Daugherty.

Greenwich LifeSciences, Stafford, TX

Background: The final analysis of the GP2 prospective, randomized, placebo-controlled, single-blinded, multicenter Phase IIb trial (NCT00524277) investigating GP2+GM-CSF versus GM-CSF alone in HLA-A02 patients administered in the adjuvant setting to node-positive and high-risk node-negative breast cancer patients with HER2 status (IHC 1-3+) is now complete with 5 year follow-up. It has been previously reported that completion of the GP2+GM-CSF Primary Immunization Series (PIS) reduced recurrence rates to 0% over a 5 year follow-up period in HER2 3+ patients, who received a standard course of trastuzumab after surgery. Here we present the final immune response results, assessing peak immunity compared to baseline and between GP2 treated patients versus placebo, including by HER2 status. Interim analyses for this trial have been previously reported by Mittendorf et al.

Methods: Each GP2-treated patient was scheduled to receive 6 GP2+GM-CSF intradermal injections over the first 6 months as part of the PIS and 4 GP2+GM-CSF booster intradermal injections every 6 months thereafter. Placebo patients received GM-CSF only intradermal injections. Immune responses to GP2 were measured over time using delayed-type-hypersensitivity (DTH) skin tests and CD8 Tcell dimer binding assays.

Results: This basket trial explored HER2 3+ patients, who received a standard course of trastuzumab after surgery, and HER2 1-2+ patients, who did not receive trastuzumab after surgery. A DTH reaction was used to assess in vivo immune responses in patients (n=145). The DTH orthogonal mean was measured 48-72 hours after injection using the sensitive ballpoint-pen method and are compared using a Wilcoxon Rank-Sum. For GP2 treated patients, there was a significant increase in DTH reactions after the PIS compared to baseline DTH reactions. The DTH orthogonal mean in GP2 treated patients at baseline had a median 0.0mm versus 10.8mm after the PIS. For patients receiving GM-CSF alone, the DTH orthogonal mean prior to and after the PIS had a median of 0.0mm. In addition, the DTH reactions after the PIS were significantly greater in GP2 treated patients than in placebo patients (10.8mm vs. 0.0mm, p=0.009) and the DTH immune response in GP2 treated patients was similar between HER2 3+ and HER2 1-2+ patients. Ex vivo immune responses were assessed by phenotypic clonal expansion assays in the majority of patients (n=114). GP2-specific CTLs were quantified using the Ig:A2 dimer assay and demonstrated a gradual expansion over time reaching statistical significance approximately 6 months after the PIS compared to baseline in the GP2 treated patients (n=53, p=0.010) but not in the control patients (n=39, p=0.165).

Conclusions: Immunological data comparing peak immunity to baseline and GP2 treated patients to placebo showed that GP2 treated patients, independent of HER2 status, experienced a significant increase in their immune response while those receiving GM-CSF only did not. Future studies may explore the use of immune responses to assess: immunogenicity of GP2 by HLA type, timing of boosters to sustain immunity, clinical site performance, and the discontinuation of treatment for non-responders.

About the AACR (Free AACR Whitepaper) Annual Meeting 2021

The AACR (Free AACR Whitepaper) is the first and largest cancer research organization dedicated to accelerating the conquest of cancer and has more than 48,000 members residing in 127 countries and territories. The AACR (Free AACR Whitepaper) Annual Meeting program covers the latest discoveries across the spectrum of cancer research — from population science and prevention; to cancer biology, translational, and clinical studies; to survivorship and advocacy — and highlights the work of the best minds in research and medicine from institutions all over the world.

About Breast Cancer and HER2/neu Positivity

One in eight U.S. women will develop invasive breast cancer over her lifetime, with approximately 266,000 new breast cancer patients and 3.1 million breast cancer survivors in 2018. HER2/neu (human epidermal growth factor receptor 2) protein is a cell surface receptor protein that is expressed in a variety of common cancers, including in 75% of breast cancers at low (1+), intermediate (2+), and high (3+ or over-expressor) levels.

On April 12, 2021 Genmab A/S (Nasdaq: GMAB) reported the initiation of a share buy-back program to mitigate dilution from warrant exercises and to honor our commitments under our Restricted Stock Units program (Press release, Genmab, APR 12, 2021, View Source [SID1234577893]).

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The share buy-back program is expected to be completed no later than June 30, 2021 and comprises up to 200,000 shares.

The following transactions were executed under the program from April 5, 2021 to April 9, 2021:

Details of each transaction are included as an appendix to this announcement.

Following these transactions, Genmab holds 208,977 shares as treasury shares, corresponding to 0.32% of the total share capital and voting rights.

The share buy-back program is undertaken in accordance with Regulation (EU) No. 596/2014 (‘MAR’) and the Commission Delegated Regulation (EU) 2016/1052, also referred to as the "Safe Harbour Regulation." Further details on the terms of the share buy-back program can be found in our company announcement no. 11 dated February 23, 2021.

On April 12, 2021 Oasmia Pharmaceutical AB, an innovation-focused specialty pharmaceutical company, reported final data from the dose-escalation and dose-expansion cohorts of a Phase I trial of the investigational drug candidate Cantrixil (TRX-E-002-1) at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) annual meeting (Press release, Oasmia, APR 12, 2021, View Source [SID1234577892]).

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The full Phase I data was presented in a 15-minute oral presentation by the clinical trial’s Principal Investigator, Jermaine Coward, Associate Professor, ICON Cancer Centre, located in Brisbane, Australia.

A conference call scheduled by Oasmia today at 14:00 CEST has been postponed to enable publication of the data in a peer reviewed journal.

Top-line data previously reported by Kazia Therapeutics Ltd in December 2020 from the Phase I open-label study (NCT02903771) conducted at sites in the USA and Australia confirmed that the Phase I study met its primary endpoints, establishing clinical proof of concept.

Further clinical evaluation of the data has confirmed that Cantrixil may induce ovarian cancer stem cell (OCSC) death and sensitize cancer cells to standard chemotherapy. An encouraging signal was also seen in patients with platinum-refractory ovarian cancer. The full data also confirms the maximum tolerated dose of Cantrixil to be 5.0 mg/kg when administered weekly via intraperitoneal injection.

Principal Investigator for the trial Dr. Jermaine Coward, Associate Professor, ICON Cancer Centre, commented, "Survival outcomes for patient with mid to late-stage ovarian cancer are poor when using standard cytotoxic chemotherapy and around 80% will experience disease recurrence within 2 years. This full data further underscores the potential of Cantrixil for these patients. It is particularly exciting to see a potential impact on ovarian cancer stem cells which have been heavily implicated as a potential driver of disease recurrence."

Dr. Reinhard Koenig, Oasmia’s Chief Scientific Officer added, "Oasmia has a growing pipeline of oncology programmes in clinical development. This is excellent news and supports our belief in the potential therapeutic benefits of the investigational drug candidate Cantrixil for the treatment of ovarian cancer. We look forward to progressing the programme in clinical development next year."

In March Oasmia signed an agreement with Kazia Therapeutics to acquire exclusive global development and commercialization rights for Cantrixil.

Cantrixil consists of the active molecule, a potent and selective third generation benzopyran SMETI inhibitor named TRXE-002-01, encapsulated in a cyclodextrin. It is believed to target a wide spectrum of cancer cells, including chemotherapy-resistant tumor-initiating cells that are thought to be responsible for disease relapse.

On April 12, 2021 Heat Biologics, Inc. (Nasdaq: HTBX), a clinical-stage biopharmaceutical company focused on developing first-in-class therapies to modulate the immune system, including multiple oncology product candidates and a novel COVID-19 vaccine,reported that promising new preclinical data of PTX-35 is presented at the AACR (Free AACR Whitepaper) Annual Meeting 2021 (Press release, Heat Biologics, APR 12, 2021, View Source [SID1234577891]).

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PTX5 is the company’s first antibody-based product, currently in a Phase 1 clinical trial for the treatment of patients with solid tumors. PTX-35 is a novel, potential first-in-class antibody modulating TNFRSF25 (death receptor 3), a receptor that is preferentially expressed by antigen-experienced T-cells. In a B16F10 melanoma mouse model, PTX-35 in the presence of tumor antigen supplied by Heat’s HS-110 immunotherapy, resulted in decreased regulatory T-cell suppression and enhanced T effector responses. These changes were associated with delayed tumor progression.

Jeff Wolf, Chief Executive Officer of Heat, commented, "PTX-35 is designed to harness the body’s natural antigen-specific immune activation. We believe our latest data suggest that PTX-35 can help overcome certain mechanisms of cancer immune evasion. We continue to advance our first-in-human Phase 1 study of PTX-35 in patients with solid tumors and look forward to sharing interim data later this year."

Details of the poster presentation are as follows:

Title: PTX-35, a Potential First-in-class Agonist, Reduced the Suppressive Activity of Regulatory T cells and Enhanced CD4+ T cell Effector Responses in the Presence of Tumor Antigens in a Murine Melanoma Model

Abstract Number: 604

Session: Modifiers of the Tumor Microenvironment

Presenter: Eric Dixon, Director of Discovery Sciences, Heat Biologics

About the AACR (Free AACR Whitepaper) Annual Meeting

The 2021 AACR (Free AACR Whitepaper) Annual Meeting program covers the latest discoveries across the spectrum of cancer research—from population science and prevention to cancer biology, translational, and clinical studies, as well as survivorship and advocacy—and highlights the work of the best minds in research and medicine from institutions all over the world.