On April 10, 2021 Black Diamond Therapeutics, Inc. (Nasdaq: BDTX), a precision oncology medicine company pioneering the discovery and development of small molecule, MasterKey therapies, reported the presentation of preclinical data on BDTX-189 and BDTX-1535 at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (AACR) (Free AACR Whitepaper), taking place April 9-14, 2021 (Press release, Black Diamond Therapeutics, APR 10, 2021, View Source [SID1234584639]).

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"These preclinical data demonstrate achievement of a key goal of our pharmacokinetic (PK)/pharmacodynamic (PD) strategy for BDTX-189 with a preclinical PK/PD profile designed for rapid and sustained target inhibition with rapid clearance," said Elizabeth Buck, Ph.D., Executive Vice President, Discovery and Translational Sciences at Black Diamond Therapeutics. "We look forward to presenting preliminary clinical data, including detailed PK data, from the Phase 1 dose-escalation portion of the MasterKey-01 study in the first half of this year."

Dr. Buck continued: "Additionally, these data illustrate the MasterKey profile of BDTX-1535 as a brain-penetrant, epidermal growth factor receptor (EGFR) mutant selective inhibitor. BDTX-1535 has been shown to potently and selectively inhibit the family of EGFR variants implicated in glioblastoma multiforme (GBM), as well as Exon 18 mutations and the C797S mutations evident in non-small cell lung cancer (NSCLC). This breadth of coverage, coupled with a brain-penetrant PK profile, supports the potential to develop a novel and differentiated candidate for GBM and solid tumors expressing un-drugged EGFR mutations, including NSCLC."

The presentations describe the following data:

Preclinical PK BDTX-189 Data:

Black Diamond employed a novel physiologically based pharmacokinetic (PBPK) modeling strategy, accounting for compound-specific determinants of BDTX-189 metabolism and disposition, to prospectively predict the clinical PK profile and active dose range of BDTX-189.
Preclinical PBPK modeling indicated that BDTX-189 would be readily orally absorbed with a short elimination half-life (approximately two hours) while maintaining suppression of ErbB pathway biomarkers over the dosing interval, consistent with the irreversible mechanism of action and the desired PK/PD profile.
Active dose levels in humans were projected to be in the 400–800 mg QD range based on the exposure-tumor growth inhibition relationship in multiple mouse patient-derived xenograft (PDX) models harboring ErbB allosteric mutations.
Enrollment and dosing of patients in the Phase 1/2 MasterKey-01 study of BDTX-189 is ongoing, and the Company is on track to complete the dose-escalation portion of the Phase 1 clinical trial in the first half of 2021.
Preclinical BDTX-1535 Data:

GBM tumors express a family of allosteric oncogenic EGFR variants that often appear together in GBM and, as shown by the Company’s preclinical work, must all be effectively inhibited to secure a meaningful anti-tumor response. In cell-based assays, BDTX-1535 achieved potent and selective inhibition of all members of the family of oncogenic EGFR variants expressed in GBM.
BDTX-1535 demonstrated a favorable brain-penetrant PK profile in mouse, rat, and dog models.
Tumor growth inhibition in mouse models bearing intracranial GBM6 patient-derived tumors expressing allosteric EGFR mutants was achieved.
BDTX-1535 demonstrated potent and selective inhibition of rare Exon 18 mutations and the C797S mutation, supporting the potential for utility beyond GBM, such as in NSCLC.
Black Diamond expects to file an Investigational New Drug (IND) application for BDTX-1535 in the first half of 2022.
"Collectively, these data support the differentiated profiles of both BDTX-189 and BDTX-1535, the foundation of our ErbB franchise, and our ability to develop novel therapies for patients with genetically defined cancers," said David M. Epstein, Ph.D., President and Chief Executive Officer of Black Diamond Therapeutics.

The presentations from the AACR (Free AACR Whitepaper) meeting are available on the "Scientific Presentations and Publications" section of the Black Diamond Therapeutics website.

About BDTX-189
BDTX-189 is an orally available, irreversible small molecule inhibitor that is designed to block the function of family of oncogenic proteins defined by driver mutations across a range of tumor types, and which affect both of the epidermal growth factor receptor (EGFR) and the tyrosine-protein kinase, ErbB-2, or human epidermal growth factor receptor 2 (HER2). BDTX-189 is designed as a MasterKey inhibitor targeting a family of previously undrugged and functionally similar mutations in a tumor-agnostic manner. These mutations include extracellular domain allosteric mutations of HER2, as well as EGFR and HER2 kinase domain Exon 20 insertions, and additional activating oncogenic drivers of ErbB. The ErbB receptors are a group of receptor tyrosine kinases involved in key cellular functions, including cell growth and survival. BDTX-189 is also designed to spare normal, or wild-type, EGFR, which we believe has the potential to improve upon the toxicity profiles of current ErbB kinase inhibitors. Currently, there are no medicines approved by the U.S. Food and Drug Administration (FDA) to target all of these oncogenic mutations with a single therapy.

BDTX-189 is currently being evaluated in a Phase 1/2 clinical trial (MasterKey-01) in adult patients with advanced solid tumors with at least one MasterKey mutation who have no standard therapy available or for whom standard therapy is considered unsuitable or intolerable. In July 2020, the FDA granted Fast Track designation to BDTX-189 for the treatment of adult patients with solid tumors harboring an allosteric HER2 mutation or an EGFR or HER2 Exon 20 insertion mutation who have progressed following prior treatment and who have no satisfactory treatment options.

On April 10, 2021 GlycoMimetics, Inc. (Nasdaq: GLYC) reported that a Phase 1b trial of GMI-1359, being conducted at Duke University Cancer Center, showed evidence of on-target effects, immune-activation and cell mobilization in the initial two patients treated with the Company’s dual antagonist of E-selectin and CXCR4 (Press release, GlycoMimetics, APR 10, 2021, View Source [SID1234577818]). Dorothy Sipkins, MD, PhD, Associate Research Professor in Pharmacology and Cancer Biology at Duke University School of Medicine, will present results from the proof-of-concept clinical study as well as a separate preclinical study supporting the positive biologic findings of the Phase 1b study. The presentation will be made at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) 2021 Annual Meeting, which is being held virtually on April 10-15 and May 17-21. GMI-1359 is GlycoMimetics’ novel small molecule drug candidate, a dual antagonist of E-selectin and CXCR4, designed to target tumor-microenvironment resistance to chemotherapy in cancers with bone metastases.

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The initial data from the study confirmed the dual CXCR4 and E-selectin antagonist’s on-target effects. In the two patients who completed treatment, evaluations of peripheral blood showed a consistent mobilization of CD34+ hematopoietic stem and progenitor cells at doses beginning at 5 mg/kg and a reduction of plasma levels of soluble E-selectin. Furthermore, in one individual, following the administration of 7.0 mg/kg of GMI-1359, an immunophenotyping assessment of peripheral blood showed a redistribution of myeloid derived suppressor cells (MDSCs) as evidenced by increased percentages of both the monocytic and granulocytic MDSCs. In this same individual following administration of 7.0 mg/kg GMI-1359, the incidence of M1 proinflammatory macrophages increased while the M2 anti-inflammatory macrophages, often associated with tumor progression, decreased. The clinical poster concludes that GMI-1359 demonstrated an acceptable safety and tolerability profile in the patients treated to date. No dose limiting toxicities were observed following multiple dose administration up to 7 mg/kg.

Dr. Sipkins noted, "Despite the fact that our patient numbers are very small due to COVID’s impact on recruitment, we are seeing the on-target effects of antagonizing both CXCR4 and E-selectin with use of GMI-1359, and that the drug is well-tolerated at all dose levels. Our pilot immune profile analysis also suggests that the drug could have favorable effects on the tumor immune microenvironment, echoing results seen in our preclinical work."

Dr. Sipkins will disclose preclinical evidence that it may be possible for GMI-1359 to augment immune recognition of the tumor. The data in the poster from a mouse metastatic breast carcinoma model demonstrated a reduction in the immune suppressive monocytic MDSCs at the primary tumor site and a significant increase in the CD8/Treg ratio in both the primary tumor and at the bone metastatic sites. These findings on immune cell redistributions strongly suggest the induction of a more favorable anti-tumor environment following GMI-1359 administration.

According to Dr. Eric J. Feldman, GlycoMimetics Senior Vice President and Chief Medical Officer, "The information shared in this AACR (Free AACR Whitepaper) poster provides us with important understandings upon which we expect to identify a potential indication for advancing GMI-1359 in the clinic. It suggests that this small molecule drug candidate could improve responses to therapies and potentially reduce the burden of metastatic breast cancer disease."

In prior preclinical research supported by GlycoMimetics, Dr. Sipkins’ laboratory demonstrated that E-selectin and CXCR4/SDF-1 interactions were critical for breast carcinoma cells (BCCs) invasion and retention, respectively, into bone. Moreover, they found that dormant and proliferating BCCs occupy distinct regions of the bone microenvironment, with dormant BCCs predominantly found in SDF-1 and E-selectin rich regions. These dormant BCCs are expected to be highly susceptible to GMI-1359 mobilization, suggesting a new intervention to break the foothold of dormant BC micrometastases in bone.

Details on the GMI-1359 e-presentation at the AACR (Free AACR Whitepaper) Meeting are as follows:

Title: Development of GMI-1359, a novel agent targeting tumor-microenvironment cross-talk in bone metastatic cancer
Presenter: Dorothy Sipkins, MD, PhD, Associate Research Professor in Pharmacology and Cancer Biology at Duke University School of Medicine
Session: e-Presentation
Date and Time: Saturday, April 10, 2021 (available online through Monday, June 21)

About GMI-1359

GMI-1359 is designed to simultaneously inhibit both E-selectin and CXCR4, which are adhesion molecules involved in tumor trafficking and metastatic spread. Preclinical studies indicate that targeting both E-selectin and CXCR4 with a single compound could improve efficacy in the treatment of cancers that involve the bone marrow, such as AML and multiple myeloma, or in solid tumors that metastasize to the bone, such as prostate cancer and breast cancer, as well as in osteosarcoma, a rare pediatric tumor affecting about 900 adolescents a year in the United States. GMI-1359 completed a Phase 1 clinical trial in healthy volunteers, and a Phase 1b clinical study is underway in breast cancer patients and is designed to enable investigators to identify study dose ranging and to generate initial biomarker data around the drug’s activity. In the first two patients evaluated, the study showed evidence of on-target effects, immune-activation and cell mobilization. GMI-1359 has received Orphan Drug designation and Rare Pediatric Disease designation from the FDA for the treatment of osteosarcoma.

On April 10, 2021 Advaxis, Inc. (Nasdaq: ADXS), a clinical-stage biotechnology company focused on the development and commercialization of immunotherapy products, and Precision for Medicine, a specialized services company supporting next generation approaches to drug development and commercialization, reported data on the development of a novel flow immunophenotyping assay to accurately evaluate total PD-1 expression as a pharmacodynamic marker during PD-1 blockade, and translational data demonstrating immune responses correlated to observed clinical benefit from the Company’s ongoing Phase 1/2 study evaluating ADXS-503 in combination with KEYTRUDA, presented as a poster at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 (Press release, Advaxis, APR 10, 2021, View Source [SID1234577835]). ADXS-503 is the first drug construct from the ADXS-HOT off-the-shelf, cancer-type specific, immunotherapy program which leverages Advaxis’ proprietary Lm technology platform to target hotspot mutations that commonly occur in specific cancer types as well as other proprietary, tumor-associated antigens.

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"These presented data suggest this novel immunophenotyping assay has the potential to more accurately measure pharmacodynamic biomarkers in immunotherapy," said Ken Berlin, Chief Executive Officer of Advaxis. "This assay enables the detection of both free and drug-bound PD-1 expression, independent of PD-1 receptor status or interference due to PD-1 blockade, enabling the accurate evaluation of PD-1 expression in patients undergoing treatment with pembrolizumab. We believe this is another important step forward in further understanding immune responses in patients treated with immunotherapy agents, and may provide important translational insights specific to PD-1 expression and immune modulation which may help shape treatment strategies moving forward."

Mr. Berlin continued, "The flow cytometry data confirmed the on-mechanism activation of the innate and adaptive immune systems in patients with observed clinical benefit following treatment with ADXS-503 in combination with pembrolizumab. The demonstrated proliferation and activation of NK cells and CD8 + T cells, plus increased PD-1 expression in diverse immune cells in patients achieving clinical benefit, add to the growing body of evidence which demonstrate the potential of ADXS-503 to re-sensitize or enhance responses to pembrolizumab, even in patients with prior progression. We will continue these analyses with Precision for Medicine on additional patients from our ongoing Phase 1/2 study in NSCLC, and look forward to continued progress as we build upon our previously reported efficacy results which show promising and durable clinical benefit after treatment with ADXS-503, our first off-the-shelf neoantigen immunotherapy candidate."

Key presentation highlights:

Poster presentation titled, "Evaluation of total PD-1 expression using multi-color flow cytometry in metastatic non-small cell lung cancer patients treated with multi-neoantigen vector (ADXS-503) alone and in combination of pembrolizumab to assess T-cell & T-cell memory subsets" presented by Dr.Venkat Mohanram, Senior Scientist at Precision for Medicine.

A novel multi-color flow cytometry analysis was developed to accurately identify PD-1 expression on peripheral blood mononuclear cells (PBMCs) of NSCLC patients receiving PD-1/PD-L1 blockade therapy with pembrolizumab and ADXS-503

No interference in PD-1 detection due to pembrolizumab blockage was observed, enabling the determination of PD-1 expression independent of PD-1 receptor status, with both free and drug-bound PD-1 detected

Preliminary flow cytometry data demonstrated on-mechanism activation of innate and adaptive immune responses to ADXS-503. Three patients from the ongoing Phase 1/2 with demonstrated clinical benefit of stable disease showed:

Proliferation and activation of NK cells
Increased PD-1 expression on circulating CD4+, CD8+ and NK cells
Increased counts of CD8+ T cells including proliferative, cytotoxic and memory CD8+ T cells
The Phase 1/2 clinical trial of ADXS-503 is seeking to establish the recommended dose, safety, tolerability and clinical activity of ADXS-503 administered alone and in combination with a KEYTRUDA in approximately 50 patients with NSCLC, in at least five sites across the U.S. The two dose levels with monotherapy in Part A, (1 X108 and 5 X108 CFU) have been completed. Part B with ADXS-503 (1 X108 CFU) in combination with KEYTRUDA is currently enrolling its efficacy expansion for up to 15 patients at dose level 1 (1 X108 CFU + KEYTRUDA) with the potential to proceed to dose level 2 (5 X108 CFU + KEYTRUDA) at a later date. Part C, which is evaluating ADXS-503 in combination with KEYTRUDA (1 X108 CFU + KEYTRUDA) as a first line treatment for patients with NSCLC with PD-L1 expression ≥ 1% or who are unfit for chemotherapy is currently enrolling patients.

About ADXS-HOT
ADXS-HOT is a program that leverages the Company’s proprietary Lm technology to target hotspot mutations that commonly occur in specific cancer types. ADXS-HOT drug candidates are designed to target acquired shared or "public" mutations in tumor driver genes along with other proprietary cancer-testes and oncofetal tumor-associated antigens that also commonly occur in specific cancer types. ADXS-HOT drug candidates are an off-the-shelf treatment, designed to potentially treat all patients with a specific cancer type, without the need for pretreatment biomarker testing, DNA sequencing or diagnostic testing.

On April 10, 2021 Harpoon Therapeutics, Inc. (NASDAQ: HARP), a clinical-stage immunotherapy company developing a novel class of T cell engagers, reported the availability of three poster presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Harpoon Therapeutics, APR 10, 2021, View Source [SID1234577851]). The presentations will be available beginning today at 8:30 a.m. ET through the virtual meeting website at www.aacr.org and on the Harpoon corporate website at www.harpoontx.com.

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Key findings of each of the posters are described below.

FLT3-targeting TriTACs are T cell engagers for treatment of acute myeloid leukemia
Presenter: Richard J. Austin, Ph.D., Abstract #: 2643

FLT3 RNA is found in over 95% of AML samples and FLT3 mutations are oncogenic and found in approximately 30% of AML. This provides the rationale that a FLT3-targeting T cell engager could be a valid therapeutic approach for AML. Data show that FLT3 TriTACs bind human and non-human primate FLT3, and can redirect T cells to kill FLT3 expressing cells in vitro. In addition, FLT3 TriTACs eliminate FLT3 expressing cells in a non-human primate study and are well tolerated after a single dose.

ProTriTAC is a modular and robust T cell engager prodrug platform with therapeutic index expansion observed across multiple tumor targets
Presenter: S. Jack Lin, Ph.D., Abstract #: 933

ProTriTAC is a conditionally active T cell engager platform that is designed to be preferentially active in the tumor. This enables the targeting of more broadly expressed solid tumor targets and allows T cell engagers to address more tumor types. Data presented today illustrate the consistency and the robustness of the ProTriTAC platform in vitro and in vivo as demonstrated by cell-based assays, pharmacokinetic studies in non-human primates, and therapeutic index assessments in tumor-bearing animals across multiple tumor targets. IND-enabling studies are currently underway for Harpoon’s first ProTriTAC program (HPN601).

Combinatorial antitumor effects of CD3-based trispecific T cell activating constructs (TriTACs) and checkpoint inhibitors in preclinical models
Presenter: Mary Ellen Molloy, Ph.D. Abstract #: 1573

TriTAC molecules induce PD1/PD-L1 expression on T cells which may lead to suppression of the cytolytic functions of TriTAC activated T cells. PD1 can be readily detected on T cells subsequent to the engagement of the TCR by the TriTAC molecule. Data presented today show that the combination of HPN536 with a PD-L1 inhibitor led to more potent antitumor activity in an MSLN expressing ovarian cancer xenograft model. Similar enhanced anti-tumor effects were shown in an MSLN expressing lung cancer model for HPN536 in combination with anti-PD1 or an anti-PD1 antibody. These data demonstrate the potential utility of PD1/PD-L1 blockade to enhance the potency of TriTAC mediated tumor cell killing.

"These data from Harpoon’s poster presentations at AACR (Free AACR Whitepaper) underscore the potential for further investigations of additional tumor targets, combination approaches with TriTACs, and conditionally active T cell engager prodrugs, or ProTriTACs, which may lead to greater tumor specificity, enhanced efficacy, and improved tolerability for patients," said Holger Wesche, Ph.D., chief scientific officer of Harpoon Therapeutics. "I am encouraged by these findings and look forward to future validation in the clinic."

On April 10, 2021 Bayer reported Results from the randomized, double-blind, placebo-controlled Phase III trial CHRONOS-3 show a significant improvement in progression-free survival (PFS) with the investigational combination of Aliqopa (copanlisib) and rituximab given intravenously in patients with relapsed indolent non-Hodgkin’s Lymphoma (iNHL) compared to the combination of rituximab and placebo (Press release, Bayer, APR 10, 2021, View Source [SID1234577867]). After a median follow-up of 19.2 months, patients treated with this combination had a median PFS of 21.5 months (95% CI 17.9, 33.0) versus 13.8 months in patients treated with rituximab and placebo (95% CI 10.2, 17.5), (HR=0.52, p=0.000002). No new safety signals were identified for Aliqopa in the combination arm of the study.1 The data will be presented in a Clinical Trials Plenary Session on April 10 at the virtual American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 and simultaneously published in The Lancet Oncology.

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CHRONOS-3 is a Phase III randomized, double-blind, placebo-controlled trial with the objective to evaluate whether Aliqopa in combination with rituximab is superior to placebo plus rituximab in extending PFS in patients with relapsed iNHL following at least one prior rituximab-containing therapy. Patients who had a progression-free and treatment-free interval of at least 12 months after completion of the last rituximab-containing regimen or patients unwilling/unfit or for who chemotherapy was contraindicated by reason of age, co-morbidities and/or residual toxicity were included.2

In 2017, Aliqopa was approved for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies based on the results of a single-arm, multicenter, Phase II clinical trial (CHRONOS-1).3 Accelerated approval was granted for this indication based on overall response rate (ORR). Continued approval for this indication is contingent upon verification and description of clinical benefit in a confirmatory trial.

"In clinical practice, we have seen an overall improvement in the prognosis of iNHL patients, yet relapsed disease is still a prominent treatment challenge," said Matthew J. Matasar, M.D., Medical Oncologist, Regional Care Network Medical Site Director, Memorial Sloan Kettering Cancer Center (MSK) Bergen. "The results reported with the combination of copanlisib and rituximab suggest a potential advancement for patients with these diverse types of cancers."

"Bayer is committed to putting patients’ needs first and delivering innovative treatment options that address areas of high unmet need, and clinical research is the first step in that process," said Scott Z. Fields, M.D., Senior Vice President and Head of Oncology Development at Bayer. "These data highlight the potential of Aliqopa and rituximab as a new strategy for treating these patients and we look forward to advancing regulatory discussions."

Bayer is in discussions with health authorities worldwide regarding the data from CHRONOS-3.

Additional CHRONOS-3 Data Being Presented at AACR (Free AACR Whitepaper)
In addition to the primary endpoint of PFS, data on the secondary endpoints of ORR and complete response rate (CRR) will also be presented. Best ORR for the combination of Aliqopa and rituximab was 80.8% (95% CI 76, 85) versus 47.7% (95% CI 40, 56) for rituximab and placebo (p<0.0001), with 33.9% and 14.6% of patients achieving CR, respectively. Of the relapsed iNHL patients included in the trial, 60% had FL, 20.7% marginal zone lymphoma (MZL), 10.9% small lymphocytic lymphoma (SLL) and 8.3% lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM). Analysis of the subtypes will be presented at AACR (Free AACR Whitepaper) and published in The Lancet Oncology.1

All-grade treatment-emergent adverse events (TEAEs) observed with the Aliqopa and rituximab combination that occurred in more than 20% of the patients included hyperglycemia (69.4%), hypertension (49.2%), diarrhea (33.6%), neutropenia (20.8%), nausea (22.5%) and pyrexia (20.5%). Discontinuation due to all-grade TEAEs in CHRONOS-3 for Aliqopa and rituximab was 32% versus 8% for rituximab and placebo.1

Aliqopa is an intravenous phosphatidylinositol-3-kinase (PI3K) inhibitor with predominant activity against alpha and delta isoforms the PI3K-alpha and PI3K-delta isoforms expressed in malignant B cells.4 Aliqopa is approved in the U.S. under the accelerated approval pathway for the treatment of adult patients with relapsed FL who have received at least two prior systemic therapies. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Accelerated approval was granted for this indication based on an ORR of 59% (n=61/104; 95% CI 49, 68), including 14% (15/104) of CRs from the open-label, single-arm multicenter, Phase II clinical trial (CHRONOS-1), in a total of 142 subjects, which included 104 subjects with follicular B-cell non-Hodgkin’s Lymphoma who had relapsed disease following at least two prior treatments. In the updated two-year follow-up analysis conducted on data until 16 weeks after the last patients eligible for full analysis started treatment, Aliqopa ORR was 59% (n=61; 95% CI 49, 68), including 20% CR (n=21).5 Tumor response was assessed according to the International Working Group response criteria for malignant lymphoma. Efficacy based on ORR was assessed by an Independent Review Committee.

Disclosure: This study was sponsored by Bayer AG. Dr. Matasar has received honoraria from Bayer AG and subsidiaries of Bayer AG for advising and related activities. Bayer AG also provides research funding for Dr. Matasar through Memorial Sloan Kettering Cancer Center (MSK). In addition, Dr. Matasar has received honoraria from Roche/Genentech for advising and related activities, and the company also provides research funding for him through MSK.

About Aliqopa (copanlisib) Injection3
Aliqopa (copanlisib) is indicated for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies. Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Aliqopa is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3K-α and PI3K-δ isoforms expressed in malignant B cells. Aliqopa has been shown to induce tumor cell death by apoptosis and inhibition of proliferation of primary malignant B cell lines. Aliqopa inhibits several key cell-signaling pathways, including B-cell receptor signaling, CXCR12 mediated chemotaxis of malignant B cells, and NFκB signaling in lymphoma cell lines.

IMPORTANT SAFETY INFORMATION FOR ALIQOPA (copanlisib)

Infections: Serious, including fatal, infections occurred in 19% of 317 patients treated with ALIQOPA monotherapy. The most common serious infection was pneumonia. Monitor patients for signs and symptoms of infection and withhold ALIQOPA for Grade 3 and higher infection.

Serious pneumocystis jiroveci pneumonia (PJP) infection occurred in 0.6% of 317 patients treated with ALIQOPA monotherapy. Before initiating treatment with ALIQOPA, consider PJP prophylaxis for populations at risk. Withhold ALIQOPA in patients with suspected PJP infection of any grade. If confirmed, treat infection until resolution, then resume ALIQOPA at previous dose with concomitant PJP prophylaxis.

Hyperglycemia: Grade 3 or 4 hyperglycemia (blood glucose 250 mg/dL or greater) occurred in 41% of 317 patients treated with ALIQOPA monotherapy. Serious hyperglycemic events occurred in 2.8% of patients. Treatment with ALIQOPA may result in infusion-related hyperglycemia. Blood glucose levels typically peaked 5 to 8 hours post-infusion and subsequently declined to baseline levels for a majority of patients; blood glucose levels remained elevated in 17.7% of patients one day after ALIQOPA infusion. Of 155 patients with baseline HbA1c <5.7%, 16 (10%) patients had HbA1c >6.5% at the end of treatment.

Of the twenty patients with diabetes mellitus treated in CHRONOS-1, seven developed Grade 4 hyperglycemia and two discontinued treatment. Patients with diabetes mellitus should only be treated with ALIQOPA following adequate glucose control and should be monitored closely.

Achieve optimal blood glucose control before starting each ALIQOPA infusion. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of hyperglycemia.

Hypertension: Grade 3 hypertension (systolic 160 mmHg or greater or diastolic 100 mmHg or greater) occurred in 26% of 317 patients treated with ALIQOPA monotherapy. Serious hypertensive events occurred in 0.9% of 317 patients. Treatment with ALIQOPA may result in infusion-related hypertension. The mean change of systolic and diastolic BP from baseline to 2 hours post-infusion on Cycle 1 Day 1 was 16.8 mmHg and 7.8 mmHg, respectively. The mean BP started decreasing approximately 2 hours post-infusion; BP remained elevated for 6 to 8 hours after the start of the ALIQOPA infusion. Optimal BP control should be achieved before starting each ALIQOPA infusion. Monitor BP pre- and post-infusion. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of hypertension.

Non-infectious Pneumonitis: Non-infectious pneumonitis occurred in 5% of 317 patients treated with ALIQOPA monotherapy. Withhold ALIQOPA and conduct a diagnostic examination of a patient who is experiencing pulmonary symptoms such as cough, dyspnea, hypoxia, or interstitial infiltrates on radiologic exam. Patients with pneumonitis thought to be caused by ALIQOPA have been managed by withholding ALIQOPA and administration of systemic corticosteroids. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of non-infectious pneumonitis.

Neutropenia: Grade 3 or 4 neutropenia occurred in 24% of 317 patients treated with ALIQOPA monotherapy. Serious neutropenic events occurred in 1.3%. Monitor blood counts at least weekly during treatment with ALIQOPA. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of neutropenia.

Severe Cutaneous Reaction: Grade 3 and 4 cutaneous reactions occurred in 2.8% and 0.6% of 317 patients treated with ALIQOPA monotherapy respectively. Serious cutaneous reaction events were reported in 0.9%. The reported events included dermatitis exfoliative, exfoliative rash, pruritus, and rash (including maculo-papular rash). Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of severe cutaneous reactions.

Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action, ALIQOPA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of copanlisib to pregnant rats during organogenesis caused embryo-fetal death and fetal abnormalities in rats at maternal doses as low as 0.75 mg/kg/day (4.5 mg/m2/day body surface area) corresponding to approximately 12% the recommended dose for patients. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least one month after the last dose.

Adverse Drug Reactions: Serious adverse reactions were reported in 44 (26%) patients. The most frequent serious adverse reactions that occurred were pneumonia (8%), pneumonitis (5%) and hyperglycemia (5%). Adverse reactions resulted in dose reduction in 36 (21%) and discontinuation in 27 (16%) patients. The most frequently observed adverse drug reactions (≥20%) in ALIQOPA-treated patients were: hyperglycemia (54%), leukopenia (36%), diarrhea (36%), decreased general strength and energy (36%), hypertension (35%), neutropenia (32%), nausea (26%), thrombocytopenia (22%), and lower respiratory tract infections (21%).

Drug Interactions: Avoid concomitant use with strong CYP3A inducers. Reduce the ALIQOPA dose to 45 mg when concomitantly administered with strong CYP3A inhibitors.

Lactation: Advise women not to breastfeed. Advise a lactating woman not to breastfeed during treatment with ALIQOPA and for at least 1 month after the last dose.

For important risk and use information about Aliqopa, please see the full Prescribing Information.

About CHRONOS-3
CHRONOS-3 is a Phase III randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of Aliqopa in combination with rituximab versus placebo in combination with rituximab in patients with relapsed indolent NHL who have received at least one or more lines of prior rituximab-containing therapy. Histological subtypes included in the trial were follicular lymphoma (FL), small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM), and marginal zone lymphoma (MZL). Patients who had a progression-free and treatment-free interval of at least 12 months after completion of the last rituximab-containing regimen or patients unwilling/unfit or for who chemotherapy was contraindicated by reason of age, co-morbidities and/or residual toxicity were included (NCT02367040). The study enrolled 458 participants.2

About non-Hodgkin’s Lymphoma
Non-Hodgkin’s Lymphoma (NHL) comprises a highly heterogeneous group of chronic diseases with poor prognosis. NHL is the most common hematologic malignancy and the eleventh most common cancer worldwide, with nearly 510,000 new cases diagnosed in 2018. It accounted for nearly 249,000 deaths worldwide in 2018.6,7

Indolent NHL consists of multiple subtypes, including follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), and lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM). While the disease is typically slowly growing, it can become more aggressive over time. Despite treatment advances, there remains a need for improved treatment options for the relapsed or refractory stage of the disease. After response to initial therapy, response rates and duration of response decline with subsequent lines of therapy, underscoring the need for patients whose disease has already progressed.

About Oncology at Bayer
Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The oncology franchise at Bayer now expands to six marketed products and several other assets in various stages of clinical development. Together, these products reflect the company’s approach to research, which prioritizes targets and pathways with the potential to impact the way that cancer is treated.