On June 14, 2019 Kura Oncology, Inc. (Nasdaq: KURA), a clinical-stage biopharmaceutical company focused on the development of precision medicines for oncology, reported updated interim data from the ongoing Phase 2 clinical trial of its lead drug candidate, tipifarnib, in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) (Press release, Kura Oncology, JUN 14, 2019, View Source [SID1234537077]).

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The results, which will be presented during an oral session at 16:45 CET / 10:45 am ET tomorrow at the European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress in Amsterdam, demonstrate ongoing anti-tumor activity and a manageable safety profile in advanced patients with angioimmunoblastic T-cell lymphoma (AITL) as well as non-AITL PTCL. A copy of the presentation is available on the Company’s website at www.kuraoncology.com.

"With additional follow up and new patients enrolled in the ongoing Phase 2 study, tipifarnib continues to demonstrate encouraging clinical activity in patients with relapsed or refractory PTCL who have experienced a median of three prior lines of therapy," said Francine Foss, M.D., professor of medicine at the Yale Cancer Center, and a principal investigator in the trial. "Given the grim prognosis for late-stage PTCL patients, these data are exciting because they further validate tipifarnib as a targeted therapy and the potential for CXCL12 pathway biomarkers as effective enrichment strategies in late-stage PTCL patients with few therapeutic options."

The multi-center, single-arm, open-label Phase 2 trial was designed to determine the efficacy, safety and biomarkers of activity of tipifarnib in patients with relapsed or refractory PTCL. Initially, patients were enrolled without selection in the Phase 2 trial. Based upon molecular characterization of the initial patients, the Phase 2 trial was amended to include two expansion cohorts: 1) patients with AITL, an aggressive form of T-cell lymphoma often characterized by high levels of CXCL12 expression (the AITL expansion cohort), and 2) patients with PTCL who lack a single nucleotide variation (rs2839685 A>G) in the 3’-untranslated region of the CXCL12 gene (the CXCL12 SNP+ expansion cohort).

As of the May 24, 2019 data cutoff, a total of 50 relapsed/refractory PTCL patients with a median number of three prior regimens have been enrolled in all stages of the Phase 2 trial. Key preliminary findings include:

The primary efficacy endpoint was achieved in each of the AITL and CXCL12+ expansion cohorts. Sixteen patients were treated in the AITL cohort and 15 in the CXCL12 SNP+ cohort. Among the 11 evaluable patients in the AITL extension cohort, three achieved a complete response (CR) and two achieved a partial response (PR), for an objective response rate (ORR) of 45% (31% ORR on a modified intent-to-treat basis, mITT). Among the 12 evaluable patients in the CXCL12+ expansion cohort, three achieved a CR and two achieved a PR, for an ORR of 42% (33% ORR by mITT). Two of the five responders in the CXCL12+ expansion cohort were AITL patients.

When all AITL patients (N=23) and all PTCL not otherwise specified (PTCL-NOS) with available rs2839695 data and absence of this 3’UTR variant (N=17) enrolled in all portions were taken into account, ORR were 53%/39% (PPS/mITT) for AITL and 20%/18% for CXCL12 SNP+ PTCL-NOS.

Thirty-four patients had available gene expression data. Patients with a high ratio of CXCL12 expression to its receptor CXCR4 (N=17) experienced an ORR of 47% and a clinical benefit rate of 82% (CR+PR+SD) with tipifarnib.

Next-generation sequencing of 16 AITL patients revealed a high rate of mutation/variation (50%) of the killer cell immunoglobulin-like receptors, including KIR3DL2. KIR3DL2 mutation at C336R was concurrent with Q386E and was associated with outcome from tipifarnib therapy. Four of the eight KIR3DL2 C336R/Q386E patients achieved a CR, two achieved a PR and two achieved stable disease (SD) for a CR rate of 50%, an ORR of 75% and a clinical benefit rate of 100%. Furthermore, high KIR3DL2 mutant variant allele frequency KIR3DL2 was predictive of complete response to tipifarnib in AITL. Tumors with KIR3DL2 mutations expressed low levels of CXCL5 and its receptor CXCR1 and CXCR2, a potential mechanism of resistance to tipifarnib.

Tipifarnib was generally well-tolerated in this Phase 2 trial, with adverse events consistent with its known safety profile. The most frequently observed treatment-related adverse events (grade ≥ 3) were hematology-related, including thrombocytopenia, neutropenia, leukopenia, anemia, febrile neutropenia and lymphopenia.
"We believe that these data validate our prior observations of tipifarnib as a CXCL12 pathway inhibitor and constitute the first clinical proof-of-concept of farnesyl transferase inhibitors in CXCL12-driven tumors. AITL and related lymphomas encompass approximately one-third of PTCL cases and represent a significant unmet medical need," said Antonio Gualberto, M.D., Ph.D., Head of Development and Chief Medical Officer of Kura Oncology. "We are also very encouraged by the discovery of KIR3DL2 mutations, the characterization of mechanisms of sensitivity and resistance to tipifarnib in lymphoma, and the development of robust molecular tools for the selection and/or stratification of PTCL patients. These findings are a testimony of the potential for success of our precision medicine approaches."

Poster Presentation Explores CXCL12 Overexpression in Tipifarnib Responders

Separately, Kura has been evaluating the potential to use CXCL12 pathway biomarkers to enrich for clinical activity in other hematologic malignancies. In addition to AITL, high CXCL12 expression was observed in tumors from other lymphoma patients, including patients with PTCL-NOS, diffuse large B-cell lymphoma (DLBCL) and mycosis fungoides, the most common form of cutaneous T-cell lymphoma (CTCL). Lymphoma patients with CXCL12 reference sequences also appeared to have a higher chance of clinical benefit from tipifarnib treatment. The identification of these CXCL12 reference sequences in responders to tipifarnib across multiple hematologic malignancies will be presented in a poster presentation at 17:30 CET / 11:30 am ET tomorrow at the EHA (Free EHA Whitepaper) Annual Congress in Amsterdam. A copy of the poster is also available on the Company’s website at www.kuraoncology.com.

"These data represent the first prospective validation of CXCL12 pathway biomarkers to enrich for clinical activity of tipifarnib in PTCL. We believe these data support the potential to register tipifarnib in both the AITL and PTCL-NOS patient populations, and we look forward to seeking regulatory feedback on next steps for this program," said Troy Wilson, Ph.D., President and CEO of Kura Oncology. "In addition, based on our growing body of clinical and preclinical data, we believe CXCL12 pathway biomarkers may have the potential to unlock the therapeutic value of farnesyl transferase inhibition across multiple hematologic and solid tumor indications, including DLBCL, acute myeloid leukemia (AML), CTCL and pancreatic cancer."

Conference Call and Webcast

Kura’s management will host a webcast and conference call at 8:00 a.m. ET today, June 14, 2019 to discuss the results from the Company’s Phase 2 trial of tipifarnib in PTCL. The live call may be accessed by dialing (877) 516-3514 for domestic callers or +1 (281) 973-6129 for international callers and using conference ID #1273055. A live webcast of the call will be available from the Investors and Media section of the Company’s website at www.kuraoncology.com, and will be archived there for 30 days.

About Peripheral T-Cell Lymphoma

PTCL is a rare and diverse group of aggressive lymphomas that develop from white blood cells called NK/T-cells that grow abnormally. The term PTCL is sometimes used to describe a heterogeneous group of T-cell lymphomas. The most common types of PTCL are PTCL-NOS and AITL. Significant advances in the genetic landscape of T-cell and NK-cell neoplasms as the result of genomic studies, as well as the introduction of more powerful diagnostic technologies have led to revisions in the classification and introduction of new entities. Many of the same genetic changes observed in AITL are also observed in cases of PTCL-NOS that manifest a T follicular helper (TFH) phenotype. This common genotype/phenotype has led to follicular T-cell lymphoma (FTCL) and AITL being unified under a common heading. Cases of nodal PTCL with TFH phenotype are now included in the same grouping as well. As a result, patients with the PTCL-NOS phenotype are increasingly being characterized as having AITL and/or related tumors.

Recently, the U.S. Food and Drug Administration (FDA) approved ADCETRIS (brentuximab vedotin) in combination with chemotherapy for previously untreated systemic ALCL or other CD30-expressing PTCL, including AITL and PTCL-NOS. This was the first FDA-approved frontline treatment for PTCL. Previously approved therapies in relapsed or refractory PTCL were based on single-arm clinical trials of 130 patients or fewer with response rates in the range of 25-27% and limited duration of clinical benefit in unselected populations.

About CXCL12

CXCL12 is a stroma-derived chemokine that promotes the progression of lymphoma as well as other hematological and solid tumors carrying the CXCR4 receptor. Results from ancillary studies show that high CXCL12 expression is a negative prognostic factor for standard-of-care PTCL therapy. Approximately 50% of the AITL patients and 35% of the non-AITL patients in Kura’s Phase 2 trial of tipifarnib in PTCL overexpressed CXCL12.

About Tipifarnib

Kura Oncology’s lead drug candidate, tipifarnib, is a potent, selective and orally bioavailable inhibitor of farnesyl transferase in-licensed from Janssen in December 2014. Previously, tipifarnib was studied in more than 5,000 cancer patients and showed compelling and durable anti-cancer activity in certain patient subsets; however, no molecular mechanism of action had been determined that could explain its clinical activity across a range of solid tumor and hematologic indications. Leveraging advances in next-generation sequencing as well as emerging information about cancer genetics and tumor biology, Kura is seeking to identify those patients most likely to benefit from tipifarnib. In November 2018, following an end of Phase 2 meeting with the FDA, Kura initiated its first registration-directed trial of tipifarnib in patients with recurrent or metastatic HRAS mutant head and neck squamous cell carcinoma (HNSCC).

In 2018, the U.S. Patent and Trademark Office issued new patents for tipifarnib as a method of treating patients certain CXCL12-expressing cancers, including PTCL, and as a method of treating patients with AITL. Both patents expand protection for tipifarnib, providing exclusivity in the United States to 2037.

On June 14, 2019 Bristol-Myers Squibb Company (NYSE: BMY) reported the presentation of updated data from ELOQUENT-3, the international randomized Phase 2 study evaluating Empliciti (elotuzumab) plus pomalidomide and dexamethasone (EPd) versus pomalidomide and dexamethasone (Pd) alone in patients with relapsed or refractory multiple myeloma (RRMM) (Press release, Bristol-Myers Squibb, JUN 14, 2019, View Source [SID1234537076]). In a non-prespecified analysis conducted to provide a descriptive assessment of overall survival (OS) after extended follow-up of at least 18.3 months, patients treated with EPd continued to experience sustained and clinically relevant OS and progression-free survival (PFS) benefits compared with patients treated with Pd.

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Treatment with EPd was associated with a 46% reduction in risk of death [Hazard Ratio (HR) 0.54; 95% Confidence Interval (CI): 0.30 to 0.96] versus treatment with Pd alone. At 18 months, rates of OS, a secondary endpoint, were 68% for patients treated with EPd compared to 49% for patients treated with Pd. Median OS was not reached with EPd [95% CI: 24.9 months, Not Estimable (NE)] at the time of analysis and was 17.4 months (95% CI: 13.8, NE) among patients receiving Pd. Eighteen-month PFS rates were 34% among patients randomized to EPd compared to 11% among patients randomized to Pd. Safety results for EPd were consistent with the primary analysis and with prior findings for Empliciti and pomalidomide regimens.

These data will be presented at the 24th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Amsterdam in a poster display (Abstract #PS1370) on Saturday, June 15 from 5:30-7 PM CEST.

"Multiple myeloma is a disease characterized by relapse, making it all the more important to have effective options available for patients after initial treatments. With 18 months of follow-up from the ELOQUENT-3 trial, we continue to see meaningful improvements across key endpoints with EPd versus Pd alone, including a positive trend in overall survival," said Meletios A. Dimopoulos, M.D., professor and chairman of the Department of Clinical Therapeutics at Kapodistrian University of Athens School of Medicine. "These data point to the potential for this combination to become a new standard of care for patients with multiple myeloma that returned after or did not respond to prior therapies, including lenalidomide and a proteasome inhibitor."

"The extended follow-up results from ELOQUENT-3 reinforce the EPd combination’s sustained efficacy and favorable safety profile in patients with relapsed or refractory multiple myeloma," said Fouad Namouni, M.D., head, Oncology Development, Bristol-Myers Squibb. "These data, along with our overall presence at EHA (Free EHA Whitepaper), underscore our commitment to leading innovative research in hematology and developing therapies that can improve long-term survival for patients with different types of blood cancer."

Data from the primary analysis of ELOQUENT-3 were published in the New England Journal of Medicine in November 2018 and supported the approval of EPd by the U.S. Food and Drug Administration for the treatment of adult patients with RRMM who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

Bristol-Myers Squibb and AbbVie are co-developing Empliciti, with Bristol-Myers Squibb solely responsible for commercial activities.

About ELOQUENT-3

The Phase 2 ELOQUENT-3 trial randomized 117 patients with RRMM who received two or more prior therapies and were either refractory or relapsed and refractory to lenalidomide and a proteasome inhibitor. Patients were randomized 1:1 to receive either EPd (n=60) or Pd (n=57) in 28-day cycles until disease progression or unacceptable toxicity. Patients in both the EPd and Pd arms received 4 mg of pomalidomide for days 1-21 of each cycle, and the weekly equivalent of 40 mg or 20 mg dexamethasone for patients ≤75 years or >75 years, respectively. In the EPd arm, Empliciti was administered intravenously at the dose of 10 mg/kg weekly for the first 2 cycles and 20 mg/kg every four weeks starting from cycle 3. The primary endpoint of the study was investigator-assessed PFS.

In the 18-month follow-up analysis, adverse events (AEs) were comparable between treatment arms and consistent with the primary analysis. The most common grade 3-4 AEs were infections (22% among patients receiving EPd, 24% among patients receiving Pd), neutropenia (13%, 29%), anemia (10%, 22%), thrombocytopenia (10%, 7%) and hyperglycemia (8%, 11%). Grade 5 all-cause AEs occurred in seven patients (12%) who received EPd and nine patients (16%) who received Pd.

Bristol-Myers Squibb: Advancing Oncology Research

At Bristol-Myers Squibb, patients are at the center of everything we do. The focus of our research is to increase quality, long-term survival for patients and make cure a possibility. Through a unique multidisciplinary approach powered by translational science, we harness our deep scientific experience in oncology and Immuno-Oncology (I-O) research to identify novel treatments tailored to individual patient needs. Our researchers are developing a diverse, purposefully built pipeline designed to target different immune system pathways and address the complex and specific interactions between the tumor, its microenvironment and the immune system. We source innovation internally, and in collaboration with academia, government, advocacy groups and biotechnology companies, to help make the promise of transformational medicines, like I-O, a reality for patients.

About Empliciti

Empliciti is an immunostimulatory antibody that specifically targets Signaling Lymphocyte Activation Molecule Family member 7 (SLAMF7), a cell-surface glycoprotein. SLAMF7 is expressed on myeloma cells independent of cytogenetic abnormalities. SLAMF7 also is expressed on Natural Killer cells, plasma cells and at lower levels on specific immune cell subsets of differentiated cells within the hematopoietic lineage.

Empliciti has a dual mechanism of action. It directly activates the immune system through Natural Killer cells via the SLAMF7 pathway. Empliciti also targets SLAMF7 on myeloma cells, tagging these malignant cells for Natural Killer cell-mediated destruction via antibody-dependent cellular toxicity.

Empliciti was initially approved by the FDA in 2015 in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior therapies.

U.S. FDA-APPROVED INDICATIONS FOR EMPLICITI

EMPLICITI (elotuzumab) is indicated in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received one to three prior therapies.

EMPLICITI (elotuzumab) is indicated in combination with pomalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.

IMPORTANT SAFETY INFORMATION

Infusion Reactions

Infusion reactions were reported in 10% of patients treated with EMPLICITI in the ELOQUENT-2 trial [EMPLICITI + lenalidomide + dexamethasone (ERd) vs lenalidomide + dexamethasone (Rd)] and 3.3% in the ELOQUENT-3 trial [EMPLICITI + pomalidomide + dexamethasone (EPd) vs pomalidomide + dexamethasone (Pd)].

In the ELOQUENT-2 trial, all infusion reactions were Grade 3 or lower, with Grade 3 infusion reactions occurring in 1% of patients. The most common symptoms included fever, chills, and hypertension. Bradycardia and hypotension also developed during infusions. In the trial, 5% of patients required interruption of the administration of EMPLICITI for a median of 25 minutes due to infusion reactions, and 1% of patients discontinued due to infusion reactions. Of the patients who experienced an infusion reaction, 70% (23/33) had them during the first dose.

In the ELOQUENT-3 trial, the only infusion reaction symptom was chest discomfort (2%), which was Grade 1. All the patients who experienced an infusion reaction had them during the first treatment cycle.

If a Grade 2 or higher infusion reaction occurs, interrupt the EMPLICITI infusion and institute appropriate medical and supportive measures. If the infusion reaction recurs, stop the EMPLICITI infusion and do not restart it on that day. Severe infusion reactions may require permanent discontinuation of EMPLICITI therapy and emergency treatment.

Premedicate with dexamethasone, H1 blocker, H2 blocker, and acetaminophen prior to EMPLICITI infusion.

Infections

In the ELOQUENT-2 trial (N=635), infections were reported in 81% of patients in the ERd arm and 74% in the Rd arm. Grade 3-4 infections were 28% (ERd) and 24% (Rd). Discontinuations due to infections were 3.5% (ERd) and 4.1% (Rd). Fatal infections were 2.5% (ERd) and 2.2% (Rd). Opportunistic infections were reported in 22% (ERd) and 13% (Rd). Fungal infections were 10% (ERd) and 5% (Rd). Herpes zoster was 14% (ERd) and 7% (Rd).

In the ELOQUENT-3 trial (N=115), infections were reported in 65% of patients in both the EPd arm and the Pd arm. Grade 3-4 infections were reported in 13% (EPd) and 22% (Pd). Discontinuations due to infections were 7% (EPd) and 5% (Pd). Fatal infections were 5% (EPd) and 3.6% (Pd). Opportunistic infections were reported in 10% (EPd) and 9% (Pd). Herpes zoster was reported in 5% (EPd) and 1.8% (Pd).

Monitor patients for development of infections and treat promptly.

Second Primary Malignancies

In the ELOQUENT-2 trial (N=635), invasive second primary malignancies (SPM) were 9% (ERd) and 6% (Rd). The rate of hematologic malignancies was the same between ERd and Rd treatment arms (1.6%). Solid tumors were reported in 3.5% (ERd) and 2.2% (Rd). Skin cancer was reported in 4.4% (ERd) and 2.8% (Rd).

In the ELOQUENT-3 trial (N=115), invasive SPMs were 0% (EPd) and 1.8% (Pd).

Monitor patients for the development of SPMs.

Hepatotoxicity

In the ELOQUENT-2 trial (N=635), AST/ALT >3X the upper limit, total bilirubin >2X the upper limit, and alkaline phosphatase <2X the upper limit were 2.5% (ERd) vs 0.6% (Rd). Of 8 patients experiencing hepatotoxicity, 2 patients discontinued treatment while 6 patients had resolution and continued. Monitor liver enzymes periodically. Stop EMPLICITI upon ≥Grade 3 elevation of liver enzymes. Continuation of treatment may be considered after return to baseline values.

Interference with Determination of Complete Response

EMPLICITI is a humanized IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis and immunofixation assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and possibly relapse from complete response in patients with IgG kappa myeloma protein.

Pregnancy/Females and Males of Reproductive Potential

There are no available data on EMPLICITI use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage.

There is a risk of fetal harm, including severe life-threatening human birth defects, associated with lenalidomide and pomalidomide, and they are contraindicated for use in pregnancy. Refer to the respective product full prescribing information for requirements regarding contraception and the prohibitions against blood and/or sperm donation due to presence and transmission in blood and/or semen and for additional information.

Adverse Reactions

ELOQUENT-2 trial:

Serious adverse reactions were 65% (ERd) and 57% (Rd). The most frequent serious adverse reactions in the ERd arm compared to the Rd arm were: pneumonia (15%, 11%), pyrexia (7%, 5%), respiratory tract infection (3.1%, 1.3%), anemia (2.8%, 1.9%), pulmonary embolism (3.1%, 2.5%), and acute renal failure (2.5%, 1.9%).
The most common adverse reactions in ERd and Rd, respectively (≥20%) were fatigue (62%, 52%), diarrhea (47%, 36%), pyrexia (37%, 25%), constipation (36%, 27%), cough (34%, 19%), peripheral neuropathy (27%, 21%), nasopharyngitis (25%, 19%), upper respiratory tract infection (23%, 17%), decreased appetite (21%, 13%), and pneumonia (20%, 14%).
ELOQUENT-3 trial:

Serious adverse reactions were 22% (EPd) and 15% (Pd). The most frequent serious adverse reactions in the EPd arm compared to the Pd arm were: pneumonia (13%, 11%) and respiratory tract infection (7%, 3.6%).
The most common adverse reactions in EPd arm (≥20% EPd) and Pd, respectively, were constipation (22%, 11%) and hyperglycemia (20%, 15%).

On June 14, 2019 Novartis reported that Long-term follow-up data from the ongoing, pivotal open-label ENESTfreedom and ENESTop trials showed sustained treatment-free remission (TFR) after stopping frontline and second-line Tasigna (nilotinib) therapy in eligible adult patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase (CP) (Press release, Novartis, JUN 14, 2019, View Source [SID1234537074]). Separate data demonstrate promising results for asciminib (ABL001), an investigational allosteric BCR-ABL inhibitor, in combination with three different tyrosine kinase inhibitors (TKIs) in heavily pre-treated Ph+ CML-CP patients. The results will be presented at the 24th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Amsterdam1-4.

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"We are pleased to report many of our Tasigna clinical-trial patients continue to maintain treatment-free remission for nearly four years with a low adverse event burden," said John Tsai, MD, Head of Global Drug Development and Chief Medical Officer, Novartis. "Long-term trials like ENESTfreedom and ENESTop, as well as promising Phase I data from asciminib, are helping us to reimagine medicine and the way CML is treated."

Results from the ENESTfreedom study showed that about 44% of patients remained in TFR (84/190) for 192 weeks after stopping frontline Tasigna treatment. The treatment-free survival rate at 192 weeks was nearly 49%. About 99% (90/91) and 92% (84/91) of patients who resumed nilotinib due to loss of major molecular response (MMR) during the TFR phase regained MMR and molecular response4.5, respectively. Among 91 patients who resumed nilotinib, the most common adverse events (AEs) were nasopharyngitis (18.7%) as well as pruritus, fatigue and increased lipase (14.3% each). The majority of AEs were grade 1/21.

Consistent results were observed in the ENESTop trial: About 46% of patients remained in TFR (58/126) for 192 weeks after stopping second-line Tasigna treatment. The treatment-free survival rate at 192 weeks was over 50%. Among 59 patients who resumed nilotinib, the most common AEs were hypertension (20.3%) and arthralgia (13.6%). The majority of AEs were grade 1/22.

Novartis will also present data from a Phase I trial of asciminib in combination with ATP-competitive TKI in heavily-pretreated patients with Ph+ CML-CP. Importantly, each combination was evaluated in a dose finding study assessing different asciminib dose levels, so results are not comparable across the three treatment arms. The preliminary results showed:

Among patients who at baseline did not achieve BCR-ABL1 International Scale [IS] <1%, by 48 weeks3,4:

60% (9/15) achieved molecular response <1% in the asciminib-plus-imatinib arm, and
43% (6/14) and 56% (5/9) patients achieved molecular response <1% in the asciminib-plus-nilotinib and asciminib-plus-dasatinib arms, respectively.
In evaluable patients without MMR at baseline, by 48 weeks3,4:

42% (8/19) achieved MMR with asciminib plus imatinib with median treatment exposure of 54.6 weeks, and
31% (4/13) patients with asciminib plus nilotinib and 36% (5/14) patients with asciminib plus dasatinib, respectively, achieved MMR.
No patients with MMR at baseline lost MMR due to either of the three combination therapies. All combinations showed tolerable safety profile in heavily pretreated CML patients3,4:

Among patients who received asciminib plus imatinib, the most common any-grade AEs were nausea (32%), increased lipase (20%), as well as abdominal pain, peripheral edema and vomiting (16% each).
Among patients who received asciminib plus nilotinib, most common any-grade AEs were myalgia (35%), increased lipase (29%), and increased amylase, fatigue and pruritus (24% each).
Among patients who received asciminib plus dasatinib, most common any-grade AEs were increased lipase (35%) and diarrhea, headache and nausea (18% each).
"While the introduction of TKIs has changed the CML treatment paradigm, there remains a subset of patients who are intolerant or resistant to TKI therapy," said Jorge Cortes, MD, Deputy Chair and Professor of Medicine in the Department of Leukemia at MD Anderson Cancer Center, Houston Texas. "These initial results from combination therapy with currently available TKIs and a BCR-ABL1 inhibitor like asciminib are encouraging – and give us the potential to increase molecular response and prevent development of mutations."

Commitment to CML
Our ongoing research in Ph+ CML has helped transform the disease from a fatal leukemia to a chronic condition in most patients. Novartis maintains an unwavering commitment to scientific innovation and access to care for patients worldwide. As an organization committed to patients, Novartis continues to reimagine CML care by pursuing ambitious goals with courage, passion and commitment for the global CML community.

About Tasigna
Tasigna (nilotinib) is approved in more than 130 countries for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML) in chronic phase and with chronic and accelerated phase Ph+ CML resistant or intolerant to at least one prior therapy, including Glivec (imatinib). Tasigna is also approved for the treatment of pediatric patients with newly diagnosed Ph+ CML in the chronic phase and with resistance or intolerance to prior TKI therapy.

About asciminib
Asciminib (ABL001) is an investigational allosteric BCR-ABL inhibitor with a mechanism of action distinct from currently available TKI treatments for patients with CML. There is a broad clinical development program underway for asciminib both as a potential monotherapy such as the Phase III ASCEMBL third-line CML study and in combination with other therapies, such as the Phase II ASC4MORE study investigating asciminib plus imatinib for patients with CML-CP without deep molecular response. It is currently being studied in patients with and without genetic mutations that make them resistant to many targeted CML therapies. If proven safe and effective, asciminib has the potential to be a meaningful therapy, increasing the treatment options in CML and addressing the treatment needs of patients.

IMPORTANT SAFETY INFORMATION for TASIGNA (nilotinib) Capsules
Use with caution in patients with uncontrolled or significant cardiac disease and in patients who have or may develop prolongation of QTc. Low levels of potassium or magnesium must be corrected prior to Tasigna administration. Monitor closely for an effect on the QTc interval. Baseline ECG is recommended prior to initiating therapy and as clinically indicated. Cases of sudden death have been reported in clinical studies in patients with significant risk factors. Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors. Avoid food 2 hours before and 1 hour after taking dose.

Reactivation of hepatitis B can occur in patients who are chronic carriers of this virus after receiving TKI treatment.

Use with caution in patients with liver impairment, with a history of pancreatitis and with total gastrectomy. Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not use Tasigna. Tasigna may cause fetal harm in pregnant women. If pregnancy is planned during the treatment-free remission phase, the patient must be informed of a potential need to re-initiate treatment with Tasigna during pregnancy. Women should not breastfeed while taking Tasigna and for 2 weeks after the last dose.

Cases of cardiovascular events included ischemic heart disease-related events, peripheral arterial occlusive disease, and ischemic cerebrovascular events have been reported. Serious cases of hemorrhage from various sites including gastrointestinal were reported in patients receiving Tasigna. Grade 3 or 4 fluid retention including pleural effusion, pericardial effusion, ascites and pulmonary edema have been reported. Cases of tumor lysis syndrome have been reported in Tasigna-treated patients who were resistant or intolerant to prior CML therapy.

In pediatric patients the long-term effects of prolonged treatment with Tasigna is unknown.

Eligible patients who are confirmed to express the typical BCR-ABL transcripts, e13a2/b2a2 or e14a2/b3a2, can be considered for treatment discontinuation. Frequent monitoring of BCR-ABL transcript levels in patients eligible for treatment discontinuation must be performed with a quantitative diagnostic test validated to measure molecular response levels with a sensitivity of at least MR4.5 (BCR-ABL/ABL <=0.0032% IS). BCR-ABL transcript levels must be assessed prior to and during treatment discontinuation. Loss of major molecular response (MMR=BCR-ABL/ABL <=0.1% IS) or confirmed loss of MR4 (two consecutive measures separated by at least 4 weeks showing loss of MR4(MR4=BCR-ABL/ABL <=0.01% IS) will trigger treatment re-initiation within 4 weeks of when loss of remission is known to have occurred. It is crucial to perform frequent monitoring of BCR-ABL transcript levels and complete blood count with differential in order to detect possible loss of remission. For patients who fail to achieve MMR after three months of treatment re-initiation, BCR-ABL kinase domain mutation testing should be performed.

Musculoskeletal pain, myalgia, pain in extremity, arthralgia, bone pain and spinal pain may occur upon discontinuing treatment with Tasigna within the framework of attempting treatment-free remission.

The most frequent Grade 3 or 4 adverse events are hematological (neutropenia, thrombocytopenia, anemia) which are generally reversible and usually managed by withholding Tasigna temporarily or dose reduction. Chemistry panels, including electrolytes, lipid profile, liver enzymes, and glucose should be checked prior to therapy and periodically. Tasigna can cause increases in serum lipase. The most frequent non-hematologic adverse events were rash, pruritus, nausea, fatigue, headache, alopecia, myalgia, constipation and diarrhea.

On June 14, 2019 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that it has launched a new generic formulation of oxycodone hydrochloride hydrate injection for cancer pain treatment, Oxycodone Injections 10 mg and 50 mg "Daiichi Sankyo" (hereafter, new formulation), in Japan (Press release, Daiichi Sankyo, JUN 14, 2019, View Source [SID1234537073]).

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The new formulation is the first generic injection containing oxycodone hydrochloride, a strong opioid analgesic providing relief of moderate to severe pain in various types of cancer.

It is manufactured from drug substance to formulation solely by Daiichi Sankyo’s subsidiary in Japan, Daiichi Sankyo Propharma Co., Ltd. (marketing authorization holder).

The addition of the new formulation to our product lineup of opioid analgesics will provide another treatment option for patients suffering from cancer pain and further enhance our contribution to healthcare in Japan.

Product Summary

Product Name

Therapeutic Category

Original Brand Name

Oxycodone Injections 10 mg "Daiichi Sankyo"

Oxycodone Injections 50 mg "Daiichi Sankyo"

Cancer pain treatment

OxiFast Injection 10 mg

OxiFast Injection 50 mg

On June 14, 2019 ArQule, Inc. (Nasdaq: ARQL) reported preliminary results from the Company’s phase 1 dose escalation study for ARQ 531, an orally bioavailable, potent and reversible dual inhibitor of both wild type and C481S-mutant Bruton’s tyrosine kinase (BTK) in patients with relapsed or refractory hematologic malignancies at the 2019 European Hematology Association (EHA) (Free EHA Whitepaper) Annual Meeting in Amsterdam, the Netherlands (Press release, ArQule, JUN 14, 2019, View Source [SID1234537072]).

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"The profile of ARQ 531 continues to strengthen, and we are delighted to be able to demonstrate such compelling clinical activity at a well-tolerated dose in patients who have already exhausted available therapies," commented Dr. Brian Schwartz, Chief Medical Officer of ArQule. "We are now focused on finalizing the recommended phase 2 dose and planning for the expansion of our clinical efforts with ARQ 531 into later stage trials across multiple indications as a single agent and as a combination therapy."

"ARQ 531 was selected and extensively tested preclinically to address the emerging therapeutic need for patients who have become resistant to covalent BTK inhibitors," commented Dr. Jennifer Woyach, Associate Professor of Medicine at The Ohio State University and the Principal Investigator of the study. "The data presented in this poster provide compelling clinical proof-of-concept for this novel class of reversible BTK inhibitors and was predicted by the preclinical studies published in Cancer Discovery1 last year."

The reported data are from the ongoing phase 1, open label, single arm dose escalation study and include the first eight cohorts (n=34) at dose levels of 5, 10, 15, 20, 30, 45, 65 and 75 mg once a day in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), Richter’s Transformation, Waldenström macroglobulinemia and other B-cell Non-Hodgkin lymphomas. Cohort 8 (75 mg) enrollment is ongoing.

Key findings presented include the following:

ARQ 531 is well-tolerated through 65 mg QD
Pharmacokinetic data demonstrate a steady-state mean Cmin of above 1 µM in patients receiving ≥45 mg QD. The plasma half-life ranges from 20-30 hours
Pharmacodynamic data at doses above 20-30 mg QD is associated with complete pBTK inhibition and substantial CCL3 suppression
Robust, dose-dependent, anti-tumor activity was observed
ORR of 66% (4 responses in 6 evaluable patients) was observed in heavily pretreated R/R CLL patients, all with the BTK-C481S mutation, from cohort 7
A partial response was observed in the first patient with Richter’s Transformation, who had progressed on ibrutinib and R-CHOP, suggesting that ARQ 531’s distinct MOA is amenable to target this highly unmet medical need
A Follicular Lymphoma patient remains a confirmed PR and has been on therapy approximately two years, providing valuable initial insights into long- term safety as well as durability of response
The poster at EHA (Free EHA Whitepaper) presenting these data entitled, "A Phase 1 Dose Escalation Study of ARQ 531 in Patients with Relapsed or Refractory B-Cell Lymphoid Malignancies," is available on the company’s website at www.arqule.com/publications-presentations/.

ArQule will host a conference call and webcast for investors on Friday, June 14, 2019 at 8:00 a.m. EDT to discuss the ARQ 531 clinical data. The live webcast can be accessed in the "Investors and Media" section of our website, www.arqule.com, under "Events & Presentations" or by clicking here. You may also listen to the call by dialing 1-800-239-9838 within the U.S. or 1-323-794-2551 outside the U.S. and providing conference ID 3110780. A replay will be available two hours after the completion of the call and can be accessed in the "Investors & Media" section of our website, www.arqule.com, under "Events and Presentations."

About BTK and ARQ 531
Bruton’s tyrosine kinase, BTK, is a therapeutic target that has been clinically proven to inhibit B-cell receptor signaling in blood cancers. ARQ 531 is an orally bioavailable, potent and reversible dual inhibitor of both wild type and C481S-mutant BTK. The C481S-mutation is a known resistance mechanism for first generation irreversible BTK inhibitors. ARQ 531 has demonstrated a good safety profile, predictable PK, profound pharmacodynamic effects and emerging signs of dose-proportional clinical activity in phase 1 clinical testing.