On December 3, 2018 Tiziana Life Sciences plc (Nasdaq: TLSA / AIM: TILS), a biotechnology company focusing on the discovery and development of innovative therapeutics for inflammation and oncology indications, reported that patient enrollment in the ongoing Phase 2a clinical trial (CDKO-125A-010) is completed (Press release, Tiziana Life Sciences, DEC 3, 2018, View Source [SID1234531836]). This is a single-arm, repeated-dose, 6-month duration study to evaluate safety, tolerability and anti-tumor activity of Milciclib in Sorafenib-refractory or -intolerant patients with unresectable or metastatic HCC. Topline data from this multi-center trial, being conducted in Italy, Greece and Israel, will be available in the second quarter of 2019.

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Previously we reported interim analysis data from the first 10 patients, following 6 months of treatment, showing that Milciclib (100 mg once daily; 4 days on/3 days off every 4 weeks defining each cycle) was well-tolerated in this HCC patient population. It was concluded by an Independent Data Monitoring Committee (IDMC) that there were no major signals of tolerability concerns, and the IDMC allowed continuation of patient enrollment in the trial. Following completion of 6 months of treatment, three patients opted to continue treatment under the compassionate use program. Notably, one patient is still continuing treatment in the 14th month and the other two patients received treatment until 9th month and 13th month, respectively.

About HCC

HCC is the 5th most common cancer and the 3rd cause of cancer mortality worldwide. In 2007 the approval by the European Medical Agency (EMA) and Food and Drug Administration (FDA) of Sorafenib (Nexavar), an inhibitor of several receptor tyrosine kinases, in HCC represented the first systemic therapy for improving outcome in patients unsuitable for loco-regional and surgical therapies and created a new standard of treatment for the disease. However, although significant in respect to placebo, the benefits of Sorafenib are modest; the response rate is less than 3%, the improvement in median survival is 2-3 months and the drug-related symptoms are not ordinary. The complex multi-factorial etiology of HCC warrants a need for systemic therapies that target different signaling cascades to provide improved efficacy and safety for both naive patients presenting with unresectable, advanced stage and those who suffer recurrence after curative treatments (resection, ablation and transplantation).

About Milciclib

Milciclib (PHA-848125AC) is a small molecule inhibitor of several cyclin dependent kinases such as CDK1, CDK4, CDK5 and CDK7. CDKs are serine threonine kinases that play crucial roles in progression of the cell cycle from G1 to S phase. Overexpression of CDKs and other downstream signaling pathways that regulate cell cycles have been frequently associated with development of resistance towards chemotherapies. In a Phase 1 study, oral treatment with Milciclib was well-tolerated and the drug showed promising clinical responses in patients with advanced solid malignancies such as in NSCLC, pancreatic and colon cancer, thymic carcinoma and thymoma. Additionally, milciclib met its primary endpoint in two separate Phase 2 multi-center clinical trials (CDKO-125A-006: 72 patients and CDKO-125A-007: 30 patients) in thymic carcinoma and thymoma patients.

About Sorafenib

Sorafenib (co-developed and co-marketed by Bayer and Onyx Pharmaceuticals as Nexavar) is a small molecular multi-tyrosine kinase inhibitor drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma), HCC, and radioactive iodine resistant advanced thyroid carcinoma. Treatment with Sorafenib induces autophagy, which may suppress tumor growth. However, autophagy can also cause drug resistance.

On December 3, 2018 Anixa Biosciences, Inc. (NASDAQ: ANIX), a biotechnology company focused on using the body’s immune system to fight cancer, presented the latest data from its ongoing study focusing on early detection of breast cancer, utilizing Cchek, its artificial intelligence (AI) driven cancer detection technology, at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Special Conference on Tumor Immunology and Immunotherapy (Press release, Anixa Biosciences, DEC 3, 2018, View Source [SID1234531852]). The conference is designed to integrate multidisciplinary facets of basic cancer immunology and immunotherapy to broaden the understanding of ways to harness the immune system to address cancer. The conference was held November 27–30, 2018 in Miami Beach, Florida.

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Anixa presented data demonstrating the ability of Cchek to identify the presence of early stage breast cancer in a subject by using its AI technology to analyze a simple blood draw. The Cchek technology demonstrated a sensitivity of 89.3% when detecting early stage breast cancer (Stage I or II) and a specificity (the ability to correctly identify healthy subjects) of 94.7% when used to test blinded samples. Furthermore, Cchek was also able to detect the early stages of breast cancer (Stage 0) in subjects with biopsy-confirmed ductal carcinoma in situ (DCIS), a type of pre-cancerous/non-invasive breast lesion that often leads to invasive breast cancer, with 72% sensitivity. The presentation is available on Anixa’s website, or it may be requested by sending an email to AACR (Free AACR Whitepaper)[email protected] and including your name, title, and contact information.

"We are pleased to have made our presentation titled, Combining the immunophenotyping of MDSCs and lymphocytes with artificial intelligence (AI) to predict early stage breast cancer, at the AACR (Free AACR Whitepaper) Tumor Immunology and Immunotherapy conference. This data was focused on using our Cchek technology to detect breast cancer in its early stages, primarily stage I and II when the cancer is more easily treated. The majority of screening technologies currently used for breast cancer detection, such as mammography, have the ability to detect later stage breast malignancies rather successfully but have shown difficulty with earlier stages. A major challenge with mammography is the large number of false positives resulting in overtreatment and many unnecessary biopsies," stated Dr. Amit Kumar, President and CEO of Anixa Biosciences. "As our study continues, we hope to enable a better approach for identifying breast cancer as early as possible including even when a non-invasive breast cancer lesion is present, such as in the case of DCIS. We have previously announced that our initial commercial focus is on a prostate cancer test for which we will be meeting with the USFDA on December 17, 2018. We recently presented our latest prostate cancer data at the 33rd Annual Meeting of The Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)," added Dr. Kumar.

American Association of Cancer Research (AACR) (Free AACR Whitepaper)
The American Association of Cancer Research (AACR) (Free AACR Whitepaper) (www.aacr.org) is a 501(c)(3) public charity headquartered in Philadelphia, PA. The mission of the AACR (Free AACR Whitepaper) is to prevent and cure cancer through research, education, communication and collaboration. Through its programs and services, the AACR (Free AACR Whitepaper) fosters cancer research and related biomedical science; accelerates the dissemination of new research findings among scientists and others dedicated to the conquest of cancer; promotes science education and training; and advances the understanding of cancer causes, prevention, diagnosis and treatment throughout the world.

On December 3, 2018 Bio-Path Holdings, Inc., (NASDAQ: BPTH), a biotechnology company leveraging its proprietary DNAbilize antisense RNAi nanoparticle technology to develop a portfolio of targeted nucleic acid cancer drugs, reported that previously announced interim data from the Company’s Phase 2 study evaluating prexigebersen as a treatment for acute myeloid leukemia (AML) were presented in a poster at the 2018 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, taking place from December 1-4, 2018 in San Diego, CA (Press release, Bio-Path Holdings, DEC 3, 2018, View Source [SID1234531869]).

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Maro Ohanian, M.D., Assistant Professor of the Department of Leukemia at The University of Texas MD Anderson Cancer Center, presented the poster titled, "Interim Safety and Efficacy of Lower Intensity Induction Therapy with Intravenous Prexigebersen (BP1001) in Patients with Untreated Acute Myeloid Leukemia (AML)." The poster reviewed interim data from the Company’s open-label Phase 2 study evaluating the efficacy and safety of prexigebersen in conjunction with low-dose cytarabine (LDAC), a therapeutic regimen well established in treatment of AML patients who cannot or elect not to be treated with more intensive chemotherapy. The primary objective of the study is to determine whether the combination of prexigebersen and LDAC provides greater efficacy than what would be expected with LDAC alone in this de novo patient population.

Prexigebersen was safely administered to patients with untreated AML, who were considered unsuitable for standard chemotherapy. Of the 17 evaluable patients, there were four patients (24%) who achieved complete responses and four patients with stable disease including one patient who achieved a morphologic leukemia free state and two patients who had significantly reduced bone marrow blasts. In total, 47% of the evaluable patients showed some form of response, including stable disease, to the combination treatment. Efficacy data are encouraging in this challenging population in which the majority of patients had secondary AML or adverse-risk AML, and compares favorably to the reported CR (complete remission), CRp (complete remission with incomplete platelet recovery), and CRi (complete remission with incomplete hematologic recovery) rate with LDAC alone of 7-13%1.

"We are excited to be presenting these important data at ASH (Free ASH Whitepaper) before an audience of world-leading scientists and oncologists, as they demonstrate the potential for the combination of prexigerbesen and LDAC to safely and effectively treat these de novo AML patients, including doubling the complete response to treatment compared to LDAC treatment alone," noted Peter H. Nielsen, chief executive officer of Bio-Path. "We look forward to presenting final data from this study as we expect they will provide even better results for these patients suffering with AML."

1 Heiblig, Mediterr J Hematol 2016; Kantarjian, J Clin Oncol 2012; Dohner, Blood 2014

On December 2, 2018 Kite, a Gilead Company (Nasdaq: GILD), reported two-year efficacy and safety data from the pivotal ZUMA-1 trial of Yescarta (axicabtagene ciloleucel) in patients with refractory large B-cell lymphoma (Press release, Kite Pharma, DEC 2, 2018, View Source;p=irol-newsArticle&ID=2378930 [SID1234531786]). With a minimum follow-up of two years after a single infusion of Yescarta (median follow up of 27.1 months), 39 percent of patients were in an ongoing response. This updated analysis with at least 24 months of follow-up was presented at the Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) (ASH; Abstract #2967) and simultaneously published in The Lancet Oncology.

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This press release features multimedia. View the full release here: View Source

In October 2017, Yescarta became the first chimeric antigen receptor T (CAR T) cell therapy to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma (PMBCL), high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma. The U.S. Prescribing Information for Yescarta contains a Boxed Warning regarding the risk of cytokine release syndrome (CRS) and neurologic toxicities; see below for Important Safety Information.

At two years, the best objective response via investigator assessment (n=101) showed an overall response rate of 83 percent, with 58 percent of patients having achieved a complete response. With a median follow-up of 27.1 months, 39 percent of patients remained in response. Of the patients with an ongoing response at 12 months, 93 percent remained in response at 24 months. The median duration of response was 11.1 months; the median duration of complete response was not reached. Median overall survival was not reached.

"With aggressive cancers such as refractory large B-cell lymphoma, our primary goal is to extend the lives of patients," said Sattva S. Neelapu, MD, ZUMA-1 Co-Lead Investigator and Professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. "Outcomes with traditional standard of care for this highly refractory patient population have been extremely poor. Nearly 40 percent of patients in ZUMA-1 remain in response and half of the patients are still alive after at least two years of treatment with Yescarta."

In the two-year analysis (n=108), Grade 3 or higher CRS and neurologic events were seen in 11 percent and 32 percent of patients, respectively, and were generally reversible. Four patients developed new serious adverse events (occurring since the previous August 11, 2017 data cutoff), none of which were related to Yescarta. No new Yescarta-related CRS or neurologic events or deaths have occurred since the one-year analysis.

"The two-year point is a another major milestone for Yescarta, which has extended the lives of a significant number of patients in ZUMA-1 and has yielded important learnings that inform further research and development of CAR T therapies," said Alessandro Riva, MD, Executive Vice President, Oncology Therapeutics and Head, Cell Therapy, Gilead Sciences. "These data are not only significant for the lymphoma community, but also reinforce our leadership in cell therapy as we aim to transform the treatment of a variety of cancers with other investigational therapies in our pipeline."

Full study results are available in The Lancet Oncology:

Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial: http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30864-7/fulltext

U.S. Important Safety Information for Yescarta

BOXED WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving Yescarta. Do not administer Yescarta to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving Yescarta, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with Yescarta. Provide supportive care and/or corticosteroids as needed.
Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta REMS.
CYTOKINE RELEASE SYNDROME (CRS): CRS occurred in 94% of patients, including 13% with ≥ Grade 3. Among patients who died after receiving Yescarta, 4 had ongoing CRS at death. The median time to onset was 2 days (range: 1-12 days) and median duration was 7 days (range: 2-58 days). Key manifestations include fever (78%), hypotension (41%), tachycardia (28%), hypoxia (22%), and chills (20%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Ensure that 2 doses of tocilizumab are available prior to infusion of Yescarta. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for 4 weeks after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab or tocilizumab and corticosteroids as indicated.

NEUROLOGIC TOXICITIES: Neurologic toxicities occurred in 87% of patients. Ninety-eight percent of all neurologic toxicities occurred within the first 8 weeks, with a median time to onset of 4 days (range: 1-43 days) and a median duration of 17 days. Grade 3 or higher occurred in 31% of patients. The most common neurologic toxicities included encephalopathy (57%), headache (44%), tremor (31%), dizziness (21%), aphasia (18%), delirium (17%), insomnia (9%) and anxiety (9%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events including leukoencephalopathy and seizures occurred with Yescarta. Fatal and serious cases of cerebral edema have occurred in patients treated with Yescarta. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of neurologic toxicities. Monitor patients for signs or symptoms of neurologic toxicities for 4 weeks after infusion and treat promptly.

YESCARTA REMS: Because of the risk of CRS and neurologic toxicities, Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta REMS. The required components of the Yescarta REMS are: Healthcare facilities that dispense and administer Yescarta must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after Yescarta infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense or administer Yescarta are trained about the management of CRS and neurologic toxicities. Further information is available at www.YESCARTAREMS.com or 1-844-454-KITE (5483).

HYPERSENSITIVITY REACTIONS: Allergic reactions may occur. Serious hypersensitivity reactions including anaphylaxis may be due to dimethyl sulfoxide (DMSO) or residual gentamicin in Yescarta.

SERIOUS INFECTIONS: Severe or life-threatening infections occurred. Infections (all grades) occurred in 38% of patients, and in 23% with ≥ Grade 3. Grade 3 or higher infections with an unspecified pathogen occurred in 16% of patients, bacterial infections in 9%, and viral infections in 4%. Yescarta should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after Yescarta infusion and treat appropriately. Administer prophylactic anti-microbials according to local guidelines. Febrile neutropenia was observed in 36% of patients and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids and other supportive care as medically indicated. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

PROLONGED CYTOPENIAS: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Yescarta infusion. Grade 3 or higher cytopenias not resolved by Day 30 following Yescarta infusion occurred in 28% of patients and included thrombocytopenia (18%), neutropenia (15%), and anemia (3%). Monitor blood counts after Yescarta infusion.

HYPOGAMMAGLOBULINEMIA: B-cell aplasia and hypogammaglobulinemia can occur. Hypogammaglobulinemia occurred in 15% of patients. Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following Yescarta treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during Yescarta treatment, and until immune recovery following treatment.

SECONDARY MALIGNANCIES: Patients may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following Yescarta infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

ADVERSE REACTIONS: The most common adverse reactions (incidence ≥ 20%) include CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections-pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias.

On December 2, 2018 Aprea Therapeutics reported results at the 2018 ASH (Free ASH Whitepaper) Annual Meeting from its Phase Ib/II clinical study in MDS (Press release, Aprea, DEC 2, 2018, View Source [SID1234531805]). The ongoing study is evaluating the safety and efficacy of APR-246 in combination with azacitidine for the treatment of TP53 mutated MDS. The study is sponsored by the Moffitt Cancer Center with financial support from the MDS Foundation and the Aplastic Anemia and MDS International Foundation as administrator for the Evans MDS Clinical Research Consortium.

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The overall response rate in 20 evaluable patients was 95%, with 14 (70%) patients achieving a complete remission (CR) at data cutoff. Relative to baseline, p53 immunohistochemistry positivity, mutant TP53 variant allele frequency (VAF) and TP53 minimal residual disease (MRD) were significantly decreased at time of disease assessment. No dose-limiting toxicities have been experienced to date and no exacerbation of the expected AZA-related safety profile has been observed.

"The expanding data set from this study is very encouraging," said David Sallman, M.D., lead principal investigator of the clinical study from the Moffitt Cancer Center. "As of this latest data cutoff, responses have been achieved in nearly all patients, including a 70% complete remission rate, and accompanied by deep molecular remission in the majority of patients as assessed by serial TP53 analysis. In addition, the overall safety experience indicates that the combination regimen of APR-246 and azacitidine is both safe and well-tolerated. Comparison of the current data set to historical AZA clinical experience suggests that combination of APR-246 with AZA may offer these patients a better potential treatment option than AZA alone."

"The continued positive data from this clinical study has created the potential for a new treatment paradigm for patients with few therapeutic options," said Christian S. Schade, President and Chief Executive Officer of Aprea. "As a result of this exciting progress, Aprea expects to soon begin enrolling a randomized, controlled Phase III clinical study of APR-246 in combination with AZA for the treatment of TP53 mutated MDS."

About the Clinical Study

Eligible patients in the Phase Ib/II clinical study include HMA naïve, TP53 mutated MDS and oligoblastic acute myeloid leukemia (AML, ≤ 30% blasts). In the Phase Ib part of the clincal study, patients received APR-246 in a 3+3 dose escalation design (50, 75, 100 mg/kg lean body weight) IV daily over 4 days in a lead-in phase (days -14 to -10), followed by the same dose of APR-246 (days 1-4) and AZA 75 mg/m2 SC/IV over 7 days (days 4-10 or 4-5 and 8-12) in 28-day cycles. In the Phase II part of the clinical study, patients receive APR-246 as a 4,500 mg fixed dose IV daily (days 1-4) and AZA over 7 days (days 4-10 or 4-5 and 8-12) in 28-day cycles. Primary objective in Phase Ib part of the clinical study was safety, with AEs graded by CTCAE v4.03 and DLT assessment over 6 weeks. Secondary endpoints included response rate by IWG 2006 criteria, PFS, OS, as well as serial next generation sequencing and p53 immunohistochemistry for evaluation of clonal suppression and depth of remission. In the Phase II part of the clinical study the primary endpoint is response rate.

About Myelodysplastic Syndrome

Myelodysplastic syndromes (MDS) represents a spectrum of hematopoietic stem cell malignancies in which bone marrow fails to produce sufficient numbers of healthy blood cells. Approximately 30-40% of MDS patients progress to acute myeloid leukemia (AML) and mutation of the p53 tumor suppressor protein is thought to contribute to disease progression. Mutations in p53 are found in up to 20% of MDS and AML patients and are associated with poor overall prognosis.

About p53 and APR-246

The p53 tumor suppressor gene is the most frequently mutated gene in human cancer, occurring in approximately 50% of all human tumors. These mutations are often associated with resistance to anti-cancer drugs and poor overall survival, representing a major unmet medical need in the treatment of cancer.

APR-246 has been shown to reactivate mutant and inactivated p53 protein – by restoring wild-type p53 conformation and function – and thereby induce programmed cell death in human cancer cells. APR-246 has demonstrated pre-clinical anti-tumor activity in a wide variety of solid and hematological (blood) tumors, including MDS, AML, and ovarian cancer, among others. Additionally, strong synergy has been seen with both traditional anti-cancer agents, such as chemotherapy, as well as newer mechanism-based anti-cancer drugs and immuno-oncology checkpoint inhibitors. In addition to pre-clinical testing, a Phase I/II clinical program with APR-246 has been completed, demonstrating a favorable safety profile and both biological and confirmed clinical responses in hematological malignancies and solid tumors with mutations in the TP53 gene.