On June 16, 2017 Genmab A/S (Nasdaq Copenhagen: GEN) reported preliminary data from the ongoing Phase I/II study of tisotumab vedotin in solid tumors (GEN701) (Press release, Genmab, JUN 16, 2017, View Source [SID1234519590]). In Part 2 of the study, 11 of 34 evaluable patients in the cervical cancer cohort achieved a response; with a median time of treatment of 4.9 months, 7 responders are still ongoing or in follow up for progression. The safety profile of tisotumab vedotin was consistent with known MMAE based antibody-drug conjugates (ADC), including peripheral neuropathy and neutropenia. Additionally, conjunctivitis was identified as a tisotumab vedotin specific toxicity, which led to introducing of prophylactic management. In the cervical cancer cohort, 15 patients experienced one or more Grade 3 adverse events: gastro-intestinal related (5 patients), anemia (2 patients), infections (1 patient), neuropathy (2 patients), bleeding (2 patients), other (10 patients). Genmab is considering plans for further clinical development of tisotumab vedotin in cervical cancer. The GEN701 study is ongoing and further data in both cervical cancer and other solid tumor indications will be published at a later date.

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"The preliminary data we see in patients with cervical cancer treated with tisotumab vedotin are encouraging. We believe further development of this novel antibody-drug conjugate may be warranted in cervical cancer and are actively looking into possible next steps," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.
Genmab intends to submit data from this study for presentation at an upcoming medical conference.

About the GEN701 study
The GEN701 study is a 173 patient, two-part Phase I/II study of tisotumab vedotin in seven types of solid tumors: ovarian, cervical, endometrium, bladder, prostate, esophageal, and lung. Part 1 was a classical 3+3 dose escalation design testing various doses of tisotumab vedotin once every three weeks to establish the recommended Phase II (RP2D) and maximum tolerated dose as well as the safety profile of tisotumab vedotin. The still ongoing Part 2 of the study investigates all seven indications in parallel expansion cohorts. Patients receive 2.0 mg/kg (=RP2D) of tisotumab vedotin once every three weeks. The primary objective of this part of the study is to further investigate the safety profile of tisotumab vedotin and preliminary efficacy.

About tisotumab vedotin
Tisotumab vedotin is an antibody-drug conjugate (ADC) composed of a human antibody that binds to tissue factor (TF) conjugated to Seattle Genetics’ clinically validated cytotoxic drug MMAE. TF is a protein involved in tumor signaling and angiogenesis. Based on its high expression on many solid tumors and its rapid internalization, TF was selected as a target for an ADC approach. Tisotumab vedotin is in Phase I/II clinical development for solid tumors in two studies (GEN701 and GEN702). Genmab has a license and collaboration agreement for tisotumab vedotin with Seattle Genetics under which Seattle Genetics has the right to exercise a co-development option at the end of Phase I clinical development.

On June 16, 2017 Genmab A/S (Nasdaq Copenhagen: GEN) reported the U.S. Food and Drug Administration (FDA) has approved the use of DARZALEX (daratumumab) in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor (Press release, Genmab, JUN 16, 2017, View Source [SID1234519581]). DARZALEX is being developed under an August 2012 agreement in which Genmab granted Janssen Biotech, Inc. an exclusive worldwide license to develop, manufacture and commercialize the product. Genmab will receive milestone payments totaling USD 25 million from Janssen in connection with the approval and first commercial sale of DARZALEX under the newly expanded label. The sale is expected to occur quickly after the approval. The approval and related milestones do not impact the financial guidance issued by Genmab on May 10, 2017.

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"We are very pleased to receive the FDA’s decision to approve DARZALEX in combination with pomalidomide and dexamethasone. This offers another alternative to patients with multiple myeloma who haven’t seen lasting effects from other types of treatment," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.
The approval was based on data from the Phase I (MMY1001, EQUULEUS) study of daratumumab in combination with pomalidomide and dexamethasone in relapsed or refractory multiple myeloma.

About the EQUULEUS study
The Phase I EQUULEUS open-label study, Pom-D arm, included 103 patients with multiple myeloma who had received prior treatment with a proteasome inhibitor (PI) and an immunomodulatory agent. Patients in the study received 16 mg/kg daratumumab in combination with pomalidomide and dexamethasone. The overall response rate in the study was 59% (95% CI: 49.1%, 68.8%), with very good partial response (VGPR) achieved in 28% of patients. Complete response (CR) was achieved in 6% of patients and stringent CR (sCR) was achieved in 8% of patients. The median time to response was 1 month (range: 0.9 to 2.8 months). The median duration of response was 13.6 months (range: 0.9+ to 14.6+ months). The most frequent adverse reactions (>20%) in the study were: infusion reactions (50%), diarrhea (38%), nausea (30%), vomiting (21%), fatigue (50%), pyrexia (25%), upper respiratory tract infection (50%), muscle spasms (26%), cough (43%) and dyspnea (33%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions (Grade 3/4) reported in ≥5% patients included pneumonia (7%). The most common treatment-emergent hematology laboratory abnormalities were lymphopenia (94%), neutropenia (95%), thrombocytopenia (75%) and anemia (57%). The most common Grade 3/4 treatment-emergent hematology laboratory abnormalities were neutropenia (82%), lymphopenia (71%), anemia (30%) and thrombocytopenia (20%).

The median age of patients in the study was 64 years with 8% of patients older than 75. Patients in the study had received a median of four prior lines of therapy, and 74% of patients had received prior autologous stem cell transplant (ASCT). Eighty-nine percent of patients were refractory to lenalidomide and 71% were refractory to bortezomib; 64% of patients were refractory to bortezomib and lenalidomide.

About multiple myeloma
Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excess proliferation of plasma cells.1 Multiple myeloma is the third most common blood cancer in the U.S., after leukemia and lymphoma.2 Approximately 30,330 new patients were expected to be diagnosed with multiple myeloma and approximately 12,650 people were expected to die from the disease in the U.S. in 2016.3 Globally, it was estimated that 124,225 people would be diagnosed and 87,084 would die from the disease in 2015.4 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms which can include bone problems, low blood counts, calcium elevation, kidney problems or infections.5 Patients who relapse after treatment with standard therapies, including proteasome inhibitors or immunomodulatory agents, have poor prognoses and few treatment options.6

About DARZALEX (daratumumab)
DARZALEX (daratumumab) injection for intravenous infusion is indicated in the United States in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy; in combination with pomalidomide and dexamethasone for the treatment of with multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor (PI); and as a monotherapy for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a PI and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.7 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (FDA) approval to treat multiple myeloma. DARZALEX is indicated in Europe for use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy and as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a PI and an immunomodulatory agent and who have demonstrated disease progression on the last therapy. DARZALEX is the first human CD38 monoclonal antibody approved in Europe. For more information, visit www.DARZALEX.com.
Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. Daratumumab triggers a person’s own immune system to attack the cancer cells, resulting in rapid tumor cell death through multiple immune-mediated mechanisms of action and through immunomodulatory effects, in addition to direct tumor cell death, via apoptosis (programmed cell death). 7,8,9,10,11

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. Five Phase III clinical studies with daratumumab in relapsed and frontline multiple myeloma settings are currently ongoing, and additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma, NKT-cell lymphoma, amyloidosis, myelodysplastic syndromes and solid tumors. Daratumumab has received two Breakthrough Therapy Designations from the U.S. FDA, for multiple myeloma, as both a monotherapy and in combination with other therapies.

IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS – None

WARNINGS AND PRECAUTIONS
Infusion Reactions — DARZALEX can cause severe infusion reactions. Approximately half of all patients experienced a reaction, most during the first infusion. Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing an infusion. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema and pulmonary edema. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension.

Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt infusion for reactions of any severity and institute medical management as needed. Permanently discontinue therapy for life-threatening (Grade 4) reactions. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients following DARZALEX infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.

Interference with Serological Testing – Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type are not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX. Type and screen patients prior to starting DARZALEX.

Neutropenia – DARZALEX may increase neutropenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. DARZALEX dose delay may be required to allow recovery of neutrophils. No dose reduction of DARZALEX is recommended. Consider supportive care with growth factors.

Thrombocytopenia – DARZALEX may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. DARZALEX dose delay may be required to allow recovery of platelets. No dose reduction of DARZALEX is recommended. Consider supportive care with transfusions.

Interference with Determination of Complete Response – Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both, the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Adverse Reactions — In patients who received DARZALEX in combination with lenalidomide and dexamethasone, the most frequently reported adverse reactions (incidence ≥20%) were: neutropenia (92%), thrombocytopenia (73%), upper respiratory tract infection (65%), infusion reactions (48%), diarrhea (43%), fatigue (35%), cough (30%), muscle spasms (26%), nausea (24%), dyspnea (21%) and pyrexia (20%). The overall incidence of serious adverse events was 49%. Serious adverse reactions were pneumonia (12%), upper respiratory tract infection (7%), influenza (3%) and pyrexia (3%).

In patients who received DARZALEX in combination with bortezomib and dexamethasone, the most frequently reported adverse reactions (incidence >20%) were: thrombocytopenia (90%), neutropenia (58%), peripheral sensory neuropathy (47%), infusion reactions (45%), upper respiratory tract infection (44%), diarrhea (32%), cough (27%), peripheral edema (22%), and dyspnea (21%). The overall incidence of serious adverse events was 42%. Serious adverse reactions were upper respiratory tract infection (5%), diarrhea (2%) and atrial fibrillation (2%).
In patients who received DARZALEX in combination with pomalidomide and dexamethasone, the most frequently reported adverse reactions (incidence >20%) were: infusion reactions (50%), diarrhea (38%), nausea (30%), vomiting (21%), fatigue (50%), pyrexia (25%), upper respiratory tract infection (50%), muscle spasms (26%), cough (43%) and dyspnea (33%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions (Grade 3/4) reported in ≥5% patients included pneumonia (7%). The most common treatment-emergent hematology laboratory abnormalities were lymphopenia (94%), neutropenia (95%), thrombocytopenia (75%) and anemia (57%). The most common Grade 3/4 treatment-emergent hematology laboratory abnormalities were neutropenia (82%), lymphopenia (71%), anemia (30%) and thrombocytopenia (20%).

In patients who received DARZALEX as monotherapy, the most frequently reported adverse reactions (incidence ≥20%) were: neutropenia (60%), thrombocytopenia (48%), infusion reactions (48%), fatigue (39%), nausea (27%), back pain (23%), pyrexia (21%), cough (21%), and upper respiratory tract infection (20%). Serious adverse reactions were reported in 51 (33%) patients. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%).

DRUG INTERACTIONS
Effect of Other Drugs on daratumumab: The coadministration of lenalidomide, pomalidomide or bortezomib with DARZALEX did not affect the pharmacokinetics of daratumumab.

Effect of Daratumumab on Other Drugs: The coadministration of DARZALEX with bortezomib did not affect the pharmacokinetics of bortezomib.

On June 16, 2017 TG Therapeutics, Inc. (NASDAQ:TGTX), reported clinical data from its Phase 3 GENUINE trial of TG-1101 (ublituximab), the Company’s novel glycoengineered anti-CD20 monoclonal antibody in combination with ibrutinib, the BTK inhibitor, as well as data from the chemo-free triple combination of TGR-1202 (umbralisib), the Company’s oral, next generation PI3K delta inhibitor, TG-1101, and ibrutinib (Press release, TG Therapeutics, JUN 16, 2017, View Source [SID1234519580]). Data from these trials were presented today during oral sessions at the 14th International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland. These data sets were presented previously at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting earlier this month. Highlights from each of these data sets are included below.

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Michael S. Weiss, the Company’s Executive Chairman and Chief Executive Officer stated, "CLL patients with high-risk cytogenetics continue to represent a challenge and continue to progress more rapidly on ibrutinib than other patients. Improving ibrutinib therapy for these hard to treat patients still represents an unmet medical need. We are pleased to be the first Company to demonstrate in a randomized Phase 3 trial an approach to potentially improve outcomes for those patients. As presented today at ICML, and last week at ASCO (Free ASCO Whitepaper), the GENUINE Phase 3 trial showed that by adding TG-1101 to ibrutinib, we could improve overall response rate, CR rate, and MRD negativity in high risk patients. We believe the data provide a compelling case for accelerated approval given the demonstrated clinical benefit with limited additional safety risk, and we look forward to sharing these data formally with the FDA later this year." Mr. Weiss continued, "Additionally, at ICML today, and last week at ASCO (Free ASCO Whitepaper), we had an opportunity to present data on a triple therapy where we layered our proprietary PI3K-delta inhibitor, TGR-1202, to the TG-1101 plus ibrutinib combination, and demonstrated even further enhanced activity, with 100% ORR by iwCLL criteria and a high level of complete responses. These data further confirm our approach of building toward multi-drug regimens to enhance the outcome for patients, ideally achieving CRs and avoiding lifelong therapy. We look forward to continuing to explore unique combinations, with TG-1101 (ublituximab) plus TGR-1202 (umbralisib) or ‘U2′ as the backbone."

Highlights from today’s presentations include the following:

Oral Presentation: Ublituximab and ibrutinib for previously treated genetically high-risk chronic lymphocytic leukemia: Results of the GENUINE Phase 3 study (Abstract #101)

This presentation includes data from the GENUINE Phase 3 trial, a multicenter, randomized trial (NCT02301156), which assessed the efficacy and safety of TG-1101 plus ibrutinib versus ibrutinib alone in patients with high-risk CLL. For the trial, high-risk was defined as having any one or more of the following centrally confirmed features: 17p deletion, 11q deletion, or p53 mutation. The GENUINE study was designed to demonstrate the value of adding TG-1101, a potent next generation glycoengineered anti-CD20 monoclonal antibody to ibrutinib monotherapy in high risk CLL, and was powered to show a statistically significant improvement in ORR of 30%, with a minimal absolute detectable difference between the two arms of approximately 20%.

The trial met its primary endpoint, demonstrating a statistically significant improvement in Overall Response Rate (ORR), as assessed by blinded independent central radiology and hematology review by iwCLL (Hallek 2008) criteria, compared to ibrutinib alone in both the Intent to Treat (ITT) population (p=0.001) and Treated population (p < 0.001). Per iwCLL guidelines, all responders required confirmation of response for a minimum duration of 2 months. The ITT population includes all 126 randomized patients (64 in the TG-1101 plus ibrutinib arm and 62 in the ibrutinib alone arm) while the Treated population includes all ITT patients that received at least one dose of either study drug (59 in the TG-1101 plus ibrutinib arm and 58 in the ibrutinib alone arm).

Patient Demographics

One hundred and twenty-six (126) patients were randomized on the GENUINE Phase 3 Trial. 100% of patients were high risk and had either 17p deletion, 11q deletion or p53 mutation. Sixty-four percent (64%) of patients in the TG-1101 plus ibrutinib arm and 66% of patients in the ibrutinib alone arm had 17p deletion and/or a p53 mutation while 36% and 34% of patients in the TG-1101 plus ibrutinib and ibrutinib alone arms, respectively, had an 11q deletion only. The median age of patients on either arm was 67 years and the median number of prior lines of therapy for either arm was 3.

Safety & Tolerability

One hundred and seventeen (117) patients were evaluable for safety (59 patients in the TG-1101 plus ibrutinib arm, and 58 patients in the ibrutinib alone arm). The combination was well tolerated and, apart from infusion related reactions, the addition of TG-1101 did not appear to alter the safety profile of ibrutinib monotherapy. Neutropenia, occurring in 9% of patients, was the most commonly reported Grade 3/4 Adverse Event (AE) in the combination arm, followed by infusion related reactions and anemia, each reported in 5% of patients. Notably, the majority of infusion related reactions (IRR) were Grade 1 or 2 in severity, with only 5% Grade 3/4 IRR observed. Median follow-up for this study was approximately 11.4 months.

Clinical Activity

Response Rates

TG-1101 plus ibrutinib ibrutinib P-value
Treated Population (n) n=59 n=58
Overall Response Rate (ORR) 78 % 45 % P < 0.001
Complete Response (CR) 7 % 0 % NS
MRD-Negative 19%
(n=53) * 2%
(n=53) * P < 0.01
*Patients evaluable for MRD included those enrolled > 4 months prior to data cutoff date of February 15, 2017. MRD analyzed by central lab, 7-color flow cytometry

In addition to the improvements in ORR, CR, and MRD-negativity, a trend in improvement of Progression-Free Survival (PFS) in the combination arm of TG-1101 plus ibrutinib as compared to ibrutinib alone, however it was not statistically significant at the time of the analysis.

ABOUT THE PHASE 3 GENUINE STUDY

The Phase 3 GENUINE study is a randomized, open label, multicenter clinical trial to evaluate the safety and efficacy of TG-1101 (ublituximab) plus ibrutinib compared to ibrutinib alone in adult patients with high risk Chronic Lymphocytic Leukemia (CLL) who received at least one prior therapy for their disease.

The study was conducted at 160 clinical trial sites in the US and Israel and randomized 126 patients. Patients received ibrutinib orally at 420 mg once daily in both arms and in the treatment arm those patients also received intravenous infusions of TG-1101 at 900 mg dosed on days 1, 8 and 15 of cycle 1 and day 1 of cycles 2-6. Patients in the treatment arm who had not progressed received quarterly infusions of TG-1101 maintenance at 900 mg.

Oral Presentation: Chemo-free triplet combination of TGR-1202, ublituximab, and ibrutinib is well tolerated and highly active in patients with advanced CLL and NHL (Abstract #102)

This oral presentation includes data from patients with Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) and Non-Hodgkin’s Lymphoma (NHL) treated with the triple combination of TGR-1202, TG-1101 and ibrutinib. All patients were relapsed or refractory to prior therapy, except 3 CLL patients who were treatment naïve. Three cohorts for each CLL/SLL and NHL were evaluated with TGR-1202 dose escalation starting with doses of 400 mg (cohort 1), followed by 600 mg (cohort 2) and 800 mg (cohort 3), in combination with TG-1101 at 900 mg and ibrutinib daily at 420 mg (CLL) and 560 mg (NHL).

Safety & Tolerability
Thirty-eight (38) patients were evaluable for safety (20 CLL/SLL patients, and 18 NHL patients). The triple combination appeared to be well tolerated in all patients, with neutropenia (32% all grades, 18% Grade 3/4) and pneumonia (18% all grades, 11% Grade 3/4), being the only Grade 3/4 AEs in > 10% of patients. Of the 38 patients treated to date, only two AEs (sepsis and pneumonia) led to treatment discontinuation. Median time on study was 11.1 months (range 0.4 – 30+ months) with 81% of patients on study > 6 months.

Clinical Activity
Clinical activity was observed at all dose levels with 36 of 38 patients evaluable for efficacy (19 CLL/SLL patients, and 17 NHL patients), with 2 patients having discontinued prior to first efficacy assessment (1 pneumonia, and 1 investigator discretion).

CLL/SLL Efficacy highlights include:

100% (19 of 19) Overall Response Rate (ORR), including a 32% Complete Response (CR) rate observed in patients with CLL/SLL (4 of 6 CR’s pending bone marrow confirmation)
50% of the CLL patients had a 17p and/or 11q deletion
3 CLL patients had prior BTK and/or PI3Kδ inhibitor therapy, including one patient refractory to both idelalisib and ibrutinib who attained a complete response (ongoing for 1.5+ years)
NHL Efficacy highlights include:

Response Rates observed in patients with NHL:
• 100% (2 of 2) ORR, including one CR in patients with Marginal Zone Lymphoma (MZL)
• 100% (4 of 4) ORR, including 50% CR rate in patients with Mantle Cell Lymphoma (MCL)
• 80% (4 of 5) ORR, including 20% CR rate in patients with Follicular Lymphoma (FL)
• 17% (1 of 6) ORR in patients with Diffuse Large B-cell Lymphoma (DLBCL)
FL patients were heavily pretreated including 2 with prior Autologous Stem Cell Transplant (ASCT), 1 refractory to prior ibrutinib, and 1 with 5 prior lines of rituximab based therapy
DLBCL patients had a median of 4 prior therapies, and 4 of 6 were of non-GCB subtype
PRESENTATION DETAILS:

The above referenced presentations are now available on the Publications page, located within the Pipeline section, of the Company’s website at www.tgtherapeutics.com/publications.cfm.

On June 16, 2017 DelMar Pharmaceuticals (Nasdaq: DMPI) ("DelMar" and "The Company"), a biopharmaceutical company focused on the development of unique new cancer therapies designed to save and improve lives, reported the presentation of a poster at The Society for Neuro-Oncology’s 4th Pediatric Neuro-Oncology Basic and Translational Research Conference (Press release, DelMar Pharmaceuticals, JUN 16, 2017, View Source [SID1234519573]). The forum takes place at the Wyndham New Yorker Hotel in New York City on June 15-16, 2017.

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The Company’s presentation entitled "Dianhydrogalactitol (VAL-083) overcomes p53-mediated chemo-resistance and displays synergy with topoisomerase inhibitors" was presented the evening of Thursday, June 15.

The authors highlight the current absence of a viable standard-of-care for patients with pediatric high-grade gliomas (pHGG). This is because the only approved agent for this indication, temozolomide (TMZ), is rendered inactive due to pediatric brain tumors having a high expression of a TMZ-inactivating enzyme called MGMT* and a low expression of the TMZ-activating MMR** pathway proteins.

In prior clinical trials, DelMar Pharmaceuticals’ lead product candidate VAL-083 demonstrated activity against this dire pediatric cancer. The poster emphasizes the fact that VAL-083 maintains functionality regardless of the MGMT or MMR status of pHGG, and is also not affected by the p53 status of the cancer cells. In vitro, VAL-083 has been shown to cause a robust and irreversible S/G2 arrest of the cancer cells, potentially then leading to cancer cell apoptosis. The poster provides the rationale for a detailed clinical investigation of VAL-083 in pediatric high-grade gliomas both as a single agent or in combination with currently available therapies such as TMZ or topoisomerase inhibitors.

*MGMT= 06-methylguanine-DNA methyltransferase
**MMR= mismatch repair

"DelMar Pharmaceuticals is excited to share the promising horizon that VAL-083 results have shown in the treatment of pediatric brain tumor," said Jeffrey Bacha, chairman & CEO of DelMar. "We are conscious of the difference VAL-083 could make in the lives of patients and their families, and we are driven by the determination of improving patient outcomes. We are confident that our research efforts will make an impactful contribution to the community and this area of science."

About VAL-083

Dianhydrogalactitol (VAL-083) is a "first-in-class", DNA-targeting agent that introduces interstrand DNA cross-links at the N7-position of guanine leading to DNA double-strand breaks and cancer cell death. VAL-083 has demonstrated clinical activity against a range of cancers including GBM in historical clinical trials sponsored by the U.S. National Cancer Institutes.

VAL-083 has been granted an orphan drug designation by the U.S. FDA Office of Orphan Products for the treatment of glioma, medulloblastoma and ovarian cancer, and in Europe for the treatment of malignant gliomas.

DelMar has demonstrated that VAL-083’s anti-tumor activity against GBM is unaffected by the expression of MGMT in vitro. Further details regarding these studies can be found at View Source

DelMar’s recent outcomes in Phase 1-2 clinical trials suggested that VAL-083 may offer a clinically meaningful survival benefit for patients with recurrent GBM following treatment with both TMZ and bevacizumab. A well-tolerated dosing regimen of 40mg/m2/day on days 1, 2, and 3 of a 21-day cycle was selected for study in subsequent GBM clinical trials.

DelMar has embarked human clinical trials for VAL-083 across every line of GBM therapy. These trials include, i) an ongoing single-arm, biomarker driven, Phase 2 study to determine if VAL-083 treatment of MGMT-unmethylated adult GBM patients at first recurrence/progression, prior to bevacizumab improves overall survival, compared to historical control with lomustine (clinicaltrials.gov identifier: NCT02717962). ii) A pivotal, controlled Phase 3 study in temozolomide-Avastin Recurrent GBM ("STAR-3") to evaluate overall survival versus salvage chemotherapy (clinicaltrials.gov identifier: NCT03149575). iii) A single arm, biomarker driven, Phase 2 study to confirm the tolerability and efficacy of VAL-083 in combination with radiotherapy in newly diagnosed MGMT-unmethylated GBM patients whose tumors are known to express high MGMT levels. (clinicaltrials.gov identifier: NCT03050736). The results of these studies may support a new treatment paradigm in chemotherapeutic regimens for the treatment of GBM.

About Glioblastoma Multiforme (GBM)

Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard of care includes surgery, radiation and treatment with temozolomide (TMZ), however nearly all tumors recur and the prognosis for recurrent GBM is dismal. Most GBM tumors have unmethylated promoter status for O6-methylguanine-DNA-methyltransferase (MGMT); a validated biomarker for TMZ-resistance. Second-line treatment with anti-angiogenic agent bevacizumab has not improved overall survival (OS) and 5-year survival is less than 3%.

On June 16, 2017 BeiGene, Ltd. (NASDAQ:BGNE), a clinical-stage biopharmaceutical company developing innovative molecularly targeted and immuno-oncology drugs for the treatment of cancer, reported initial clinical data from an ongoing Phase 1 trial of the Bruton’s Tyrosine Kinase (BTK) inhibitor BGB-3111 combined with the anti-CD20 antibody obinutuzumab in patients with chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL) and follicular lymphoma (FL) at the 14th International Conference on Malignant Lymphoma (14-ICML) in Lugano, Switzerland (Press release, BeiGene, JUN 16, 2017, View Source [SID1234519561]). The initial Phase 1 data demonstrate that the combination is well tolerated with an overall response rate (ORR) of 89% including complete responses (CRs) in 22% of treatment naïve (TN) CLL/SLL patients, an ORR of 92% with CRs in 16% of relapsed/refractory (R/R) CLL/SLL patients, and an ORR of 73% with CRs in 33% of R/R FL patients.

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"This clinical trial is supported by preclinical work suggesting that BGB-3111 may combine well with antibodies that rely on antibody-dependent cell-mediated cytotoxicity, such as obinutuzumab, because of less off-target inhibition of interleukin-2-inducible T-cell kinase. The preliminary clinical results to date suggest that the combination is well tolerated and highly active in patients with CLL or SLL and FL. Complete responses have already been observed in patients with both disease types, including CLL or SLL patients with high-risk features, despite a very short follow-up time," commented Constantine Tam, MD, Disease Group Lead for Low Grade Lymphoma and Chronic Lymphocytic Leukemia at Peter MacCallum Cancer Centre, Director of Haematology at St. Vincent’s Hospital, Australia, and lead author of the presentation.

"We are very pleased to report initial results from our first combination trial with BGB-3111. The preliminary complete response rate in CLL and SLL, as well as the frequency and depth of responses in FL, appear to be favorable compared to reported data with BTK inhibitors or anti-CD20 antibodies alone. Given the depth and durability of BGB-3111 monotherapy activity in our trials to date, we look forward to seeing the combination data mature over time and plan to initiate late-stage trials of this combination in FL," commented Jane Huang, MD, Chief Medical Officer, Hematology at BeiGene.

On the basis of data presented on BGB-3111, BeiGene announced that it plans to expand its global registrational program for BGB-3111 to include a Phase 2 pivotal trial of BGB-3111 in combination with obinutuzumab compared to obinutuzumab alone in patients with R/R FL. In addition, based on data with BGB-3111 monotherapy presented earlier at this meeting, BeiGene is planning to initiate a Phase III trial comparing BGB-3111 with bendamustine plus rituximab in patients with TN CLL. These two additional trials will expand the late-stage clinical trial program for BGB-3111, which includes an ongoing global Phase 3 comparison trial with ibrutinib in Waldenström’s macroglobulinemia (WM) and single-arm pivotal trials in R/R CLL/SLL and R/R mantle cell lymphoma intended to support approval of BGB-3111 in China.

Summary of Results from the Ongoing Phase 1 Trial

The multi-center, open-label Phase 1 trial of BGB-3111 with obinutuzumab in patients with B-cell malignancies is being conducted in Australia and the United States and consists of a dose-escalation phase and a dose-expansion phase in disease-specific cohorts, which include TN or R/R CLL/SLL and R/R FL. The dose-escalation component is testing BGB-3111 at 320 mg once daily (QD) or 160 mg twice daily (BID) in 28-day cycles, in combination with obinutuzumab; obinutuzumab was administered in line with standard CLL dosing (three loading doses of 1000 mg weekly followed by 1000 mg on day one of cycles 2–6). The ongoing dose-expansion component is testing doses of BGB-3111 at 160 mg BID with the same obinutuzumab schedule. As of March 31, 2017, 45 patients with CLL/SLL and 17 patients with FL were enrolled in the trial.

At the time of the data cutoff of March 31, 2017, BGB-3111 was shown to be well tolerated in both CLL/SLL and FL. The most frequent adverse events (AEs) (≥15%) of any attribution in CLL/SLL were petechiae/purpura/contusion (33%), neutropenia (31%), thrombocytopenia (22%), fatigue (18%), pyrexia (18%), upper respiratory tract infection (18%), and diarrhea (16%); all of these were grade 1 or 2 except for grade 3 or 4 neutropenia (20%) and grade 3 or 4 thrombocytopenia (4%). The most frequent AEs (≥15%) in FL were petechiae/purpura/contusion (35%), fatigue (29%), cough (18%), diarrhea (18%), dizziness (18%), headache (18%), insomnia (18%), nausea (18%), and upper respiratory tract infection (18%); all of these were grade 1 or 2. Serious AEs occurred in 24% of both the CLL/SLL and FL patients. Infusion-related reactions occurred in 24% of CLL/SLL patients and 6% of FL patients; all cases were grade 1 or 2 except for one grade 4 case in a CLL/SLL patient. There were no cases of serious hemorrhage (≥ grade 3 hemorrhage or central nervous system hemorrhage of any grade) or atrial fibrillation. Only one patient discontinued treatment due to an AE, squamous cell carcinoma (SCC), and this patient had a prior history of SCC.

At the time of the data cutoff, 43 patients with CLL/SLL (18 TN, 25 R/R) and 15 patients with R/R FL had greater than 12 weeks of follow-up and were evaluable for efficacy. In TN CLL/SLL, after a median follow-up of 7.0 months (2.8–11.8 months), the overall response rate (ORR) was 89% with complete responses (CRs) in 22% and partial responses (PRs) in 67% of patients. Stable disease (SD) was observed in 11% of patients. In R/R CLL/SLL, at a median follow-up time of 8.0 months (3.8–14.0 months) the ORR was 92% with CRs in 16% and PRs in 76% of patients. SD was observed in 4% of patients. In R/R FL, at a median follow-up time of 6.2 months (1.2–10.7 months), the ORR was 73% with CRs in 33% and PRs in 40% of patients. Stable disease was observed in 13% of patients. One patient with R/R CLL/SLL had progressive disease (Richter’s transformation), and two patients with R/R FL had progressive disease.

Investor Call and Webcast Information

BeiGene will host an investor call and webcast to discuss the data presented at 14-ICML and its development program.

Date & Time: Friday, June 16, 2017, 2:00 PM CEST (8:00 AM EDT, 8:00 PM China Standard Time)

Dial-in Numbers: 1-845-675-0437 or 1-866-519-4004 (US), 400-620-8038 or 800-819-0121 (China), +852 30186771 (Hong Kong), or +65 67135090 (International)

Conference ID Number: 33044427

A live webcast and replay will be available on BeiGene’s investor website View Source The dial-in replay will be available approximately two hours after the conference and will be available for two days following the event. It can be accessed by dialing 1-646-254-3697 (US), 400-632-2162 (China), +852 30512780 (Hong Kong), or +61 2 8199 0299 (International).

About BGB-3111

BGB-3111 is a potent and highly selective investigational small molecule inhibitor of BTK (Bruton’s Tyrosine Kinase). BGB-3111 has demonstrated higher selectivity against BTK than ibrutinib (the only BTK inhibitor currently approved by the U.S. Food and Drug Administration and the European Medicines Agency) based on biochemical assays, higher exposure than ibrutinib based on their respective Phase I experience, and sustained 24-hour BTK occupancy in both the blood and the lymph node.