On December 17, 2018 HedgePath Pharmaceuticals, Inc. (OTCQB:HPPI) reported that it has entered into a revised Supply and License Agreement (SLA) with its majority stockholder Mayne Pharma Ventures Pty Ltd (Mayne Pharma), an affiliate of Mayne Pharma Group Limited (ASX: MYX) (Press release, HedgePath Pharmaceuticals, DEC 17, 2018, View Source [SID1234532107]).

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Under the new SLA, Mayne Pharma will assume control of the regulatory and clinical development program for SUBA-Itraconazole for the treatment of basal cell carcinoma nevus syndrome (SUBA-Itraconazole BCCNS) in anticipation of conducting a global Phase 3 pivotal clinical trial based on results achieved in the Phase 2(b) trial conducted by HPPI in the U.S. Mayne Pharma will immediately assume responsibility for all future SUBA-Itraconazole BCCNS-related expenses.

In consideration of the transfer to Mayne Pharma of the SUBA-Itraconazole BCCNS clinical data and regulatory rights, HPPI will receive the following consideration:

a 9% royalty on future net sales of SUBA-Itraconazole BCCNS in the U.S. (subject to deductions for HPPI’s continuing access to certain third party patents).

$3 million of new funding in stages tied to the transfer of SUBA-Itraconazole BCCNS to Mayne Pharma. This funding, which is expected to be completed by mid-2019, will be non-dilutive since it is structured as a discounted advance on the future 9% royalties receivable by HPPI (although if SUBA-Itraconazole BCCNS is not approved in the U.S. by the end of 2023, Mayne Pharma may recapture such discounted advances in the form of common stock of HPPI at the then current market value of HPPI’s common stock).

In addition, if HPPI is able to secure $3 million in new funding from third parties by June 30, 2021, at HPPI’s election, Mayne Pharma will make additional royalty advances of up to $2 million on the same terms. This commitment by Mayne Pharma of an additional $2 million in funding may alternatively be satisfied if Mayne Pharma elects to participate in future equity financings of HPPI.

The SLA will continue in effect, and the exclusive field covered by the SLA has been focused to specifically comprise prostate, lung and certain other non-cancer proliferation disorders. Mayne Pharma will have the right to exploit SUBA-Itraconazole in all other

fields in the U.S., including BCCNS. Importantly, HPPI’s continued right to work on these indications will no longer be tied to the achievement of clinical or commercial target dates. HPPI is now working towards the submission of an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA) for SUBA-Itraconazole for the treatment of prostate cancer (SUBA-Itraconazole Prostate), with the goal of having that IND cleared, allowing HPPI to proceed to recruitment for initiating human trials.

In addition, Mayne Pharma will continue to provide quantities of SUBA-Itraconazole drug and placebo oral capsules for HPPI’s SUBA-Itraconazole Prostate clinical study, with an agreed amount to be provided without charge.

In addition, unlike under the previous SLA, Mayne Pharma has licensed to HPPI the right to use all pre-clinical or clinical trial or other data generated or owned by Mayne Pharma related to the current SUBA-Itraconazole formulation anywhere in the world for HPPI’s activities in the U.S. in a specified field under the new SLA.

In addition, Mayne Pharma has agreed that it will support a reverse stock split of HPPI’s common stock should HPPI request this in connection with HPPI’s exploration of an uplisting to a senior stock exchange and associated capital raise.

Finally, Mayne Pharma has agreed to amend the terms of its existing Series B Convertible Preferred Stock to remove Mayne Pharma’s future right to require HPPI to redeem such securities, which will allow HPPI to fully classify such preferred stock as equity on its balance sheet.

Additional details of the transaction will be available in a Current Report on Form 8-K to be filed by HPPI with the SEC.

This transaction arose out of a right of Mayne Pharma under the previous SLA to assume control of SUBA-Itraconazole BCCNS after December 31, 2018 for a 9% royalty on future net sales of SUBA-Itraconazole BCCNS in the U.S. if a New Drug Application (NDA) for SUBA-Itraconazole BCCNS was not accepted for filing by FDA by December 31, 2018. As previously announced, based on unforeseen requirements imposed by FDA in September 2018, HPPI determined that it would be unable to responsibly file the SUBA-Itraconazole BCCNS NDA by this deadline, and thus HPPI commenced negotiations with Mayne Pharma to transfer SUBA-Itraconazole BCCNS in advance of December 31, 2018 on negotiated terms beneficial to HPPI. During these negotiations, HPPI actively undertook activities aimed at filing the SUBA-Itraconazole BCCNS NDA within the timeframes required under the SLA, but ultimately concluded in its business judgment based on significant regulatory guidance that such a filing, even if it could be accomplished, would imperil the regulatory acceptance and viability of the SUBA-Itraconazole BCCNS asset to the detriment of HPPI’s shareholders. HPPI believes that Mayne Pharma’s indication that it plans to undertake a Phase 3 study of SUBA-Itraconazole BCCNS validates HPPI’s strategic conclusions related to the present transaction with Mayne Pharma.

The transaction was negotiated and approved on behalf of HPPI by a special committee of disinterested, independent members of HPPI’s Board of Directors.

Nicholas Virca, HPPI’s President and Chief Executive Officer, stated that "It has taken a considerable effort to reach these important agreements with our majority stockholder, Mayne Pharma, and we thank them for working with us to achieve this outcome. We believe, taking into consideration all of the facts and circumstances, that enabling Mayne Pharma to pursue SUBA -Itraconazole BCCNS on advantageous terms to HPPI gives us a fresh start as a research and development company, with $3 million of near term funding and the possibility of an additional $2 million, a less restrictive SLA with Mayne Pharma with no development targets or deadlines, and access to worldwide SUBA-Itraconazole data to support our future business plans."

"Moving forward, our 2019 focus is to seek a pre-IND meeting with FDA, with the goal of reaching agreement with FDA on the endpoints for initiating a clinical trial of SUBA-Itraconazole Prostate. We commissioned a market study which included interviews with key opinion leaders to help us target a potential therapy for over 27,000 men who have metastatic castrate resistant prostate cancer who are no longer responding to androgen deprivation therapy (also known as ADT). As with SUBA-Itraconazole BCCNS, we intend to follow the 505(b)(2) regulatory pathway to accelerate our clinical testing program for SUBA-Itraconazole Prostate. Our goal will be to have our IND for SUBA-Itraconazole Prostate cleared by FDA and to begin efforts in recruiting patients for the prostate clinical trial before the end of 2019" continued Mr. Virca.

"Beyond SUBA-Itraconazole, we are planning to work with other compounds for the treatment of cancer in an effort to expand our product candidate pipeline. As announced earlier this year, we hold a world-wide exclusive option from the University of Connecticut regarding its patented chemical analogues of itraconazole to treat cancerous and non-cancerous indications. These next generation formulations of itraconazole appear to have reduced off-target side effects while exhibiting improved pharmacokinetic properties and a reduced concern associated with the use of many other drugs that are contraindicated for patients receiving itraconazole. A preclinical testing program is now underway to assess the effectiveness of the lead compound in treating certain cancers via hedgehog pathway inhibition in a well-established mouse model. If the pre-clinical results prove to be encouraging, we would expect to exercise our option and to begin efforts to outsource manufacturing to produce cGMP product as part of a program to move into human testing in 2020" concluded Mr. Virca.

Scott Richards, Mayne Pharma’s Chief Executive Officer, stated "Mayne Pharma remains committed to supporting HPPI and its leadership to pursue the clinical development, registration and commercialization of SUBA-Itraconazole for the treatment of oncology indications in the U.S. The management of HPPI has successfully progressed SUBA-Itraconazole BCCNS through its first major clinical program. We believe out-licensing our SUBA-Itraconazole intellectual property in the U.S. in this focused field through the partnership with HPPI provides Mayne Pharma shareholders with a significant stake in potentially multiple novel cancer programs. We look forward to working with HPPI to further these development programs."

On December 17, 2018 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported that the first patients have been enrolled in two global Phase 3 clinical trials of its investigational anti-PD-1 antibody, tislelizumab (Press release, BeiGene, DEC 17, 2018, View Source;p=irol-newsArticle&ID=2380809 [SID1234532091]). These trials are evaluating tislelizumab combined with chemotherapy as potential first-line treatments in patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma, and in patients with unresectable, locally advanced recurrent or metastatic esophageal squamous cell carcinoma (ESCC).

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"Available data have shown promise for anti-PD-1 antibodies in patients with advanced gastric or gastroesophageal adenocarcinoma and in patients with advanced esophageal carcinoma. We are looking forward to investigating tislelizumab globally in these Phase 3 trials," said Amy Peterson, M.D., Chief Medical Officer, Immuno-Oncology, at BeiGene. "Gastric and esophageal cancers are among the most common malignancies in Asia and collectively are responsible for over 800,000 deaths annually in China1 alone. We are hopeful that these global studies of tislelizumab may ultimately lead to improved treatment options for patients diagnosed with these malignancies."

Global Phase 3 Trial in Advanced Gastric or Gastroesophageal Adenocarcinoma

The global, randomized, double-blind, placebo-controlled Phase 3 trial is designed to enroll 720 patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma. Patients will either receive 200 mg of tislelizumab or placebo combined with platinum- and fluoropyrimidine-based chemotherapy, the standard chemotherapy treatment, intravenously once every three weeks.

The co-primary endpoints will be progression-free survival (PFS) and overall survival (OS). Secondary endpoints include overall response rate (ORR), duration of response (DOR) and quality of life (QoL), as well as safety and tolerability.

Global Phase 3 Trial in Advanced ESCC

The global, randomized, double-blind, placebo-controlled Phase 3 trial is designed to enroll 480 patients with unresectable, locally advanced recurrent, or metastatic ESCC. Patients will either receive 200 mg of tislelizumab or placebo combined with platinum- and fluoropyrimidine-based chemotherapy, intravenously once every three weeks.

The co-primary endpoints will be PFS and OS. Secondary endpoints include ORR, DOR, and QoL, as well as safety and tolerability.

For more information about these trials, patients and physicians should email BeiGene at [email protected].

About Tislelizumab
Tislelizumab (BGB-A317) is an investigational humanized IgG4 anti–PD-1 monoclonal antibody specifically designed to minimize binding to FcγR on macrophages. In pre-clinical studies, binding to FcγR on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells.

Discovered by BeiGene scientists, tislelizumab is being developed as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers. The new drug application (NDA) for tislelizumab in China for patients with R/R cHL has been accepted by the China National Medical Products Administration (NMPA, formerly known as CFDA) and granted priority review status. BeiGene and Celgene Corporation have a global strategic collaboration for the development of tislelizumab in solid tumors in the United States, Europe, Japan, and the rest of world outside Asia.

On December 17, 2018 Horizon Pharma plc (Nasdaq: HZNP) reported that the company will participate in the 37th Annual J.P. Morgan Healthcare Conference (Press release, Horizon Pharma, DEC 17, 2018, View Source [SID1234532092]). Timothy P. Walbert, chairman, president and chief executive officer, will present at 4:30 p.m. PT on Jan. 8, 2019.

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The conference presentation will be webcast live and may be accessed by visiting Horizon’s website at View Source A replay of the webcast will be available for the event.

On December 17, 2018 TG Therapeutics, Inc. (NASDAQ: TGTX) and Dana-Farber Cancer Institute reported the publication of results from the multicenter Phase 1/1b trial of umbralisib (TGR-1202), TG Therapeutics’ novel once-daily PI3K delta inhibitor, in combination with ibrutinib, the oral Bruton’s tyrosine kinase (BTK) inhibitor, in Lancet Haematology (Press release, TG Therapeutics, DEC 17, 2018, View Source [SID1234532247]). This investigator-initiated trial was conducted at Dana-Farber Cancer Institute and four additional academic and community sites across the USA in collaboration with the Leukemia and Lymphoma Society Blood Cancer Research Partnership with funding by TG Therapeutics. The publication includes safety and efficacy information from a total of 42 relapsed or refractory patients, 21 with chronic lymphocytic leukemia (CLL) and 21 with mantle cell lymphoma (MCL).

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In this study, the combination of umbralisib and ibrutinib was well tolerated and consistent with the additive toxicity profile of the two drugs individually. No dose-limiting toxicities were observed, and the maximum-tolerated dose of umbralisib when combined with ibrutinib was not reached. The recommended phase 2 dose of umbralisib when given in combination with ibrutinib was 800 mg once daily. Importantly, serious immune-mediated toxicities were not observed with this combination, as had previously been reported with combinations of different agents targeting this pathway, with only one case of transient Grade 3 transaminitis and no Grade 3/4 colitis or pneumonitis. The combination of umbralisib and ibrutinib was also clinically active, with 90% of relapsed/refractory CLL patients achieving an overall response (n=19), of which 62% (n=13) achieved a partial response or partial response with lymphocytosis, and 29% (n=6) achieved a complete response. Of the 21 patients treated with MCL, 67% (n=14) achieved an overall response, of which 48% (n=10) achieved a partial response and 19% (n=4) achieved a complete response.

These data are described further in the manuscript entitled, "Umbralisib in combination with ibrutinib in patients with relapsed or refractory chronic lymphocytic leukaemia or mantle cell lymphoma: a multicenter phase 1–1b study," which was published today in Lancet Haematology. The online version of the article can be accessed at http://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(18)30196-0/fulltext.

"Our study demonstrates for the first time that it is feasible to combine two agents targeting B cell receptor pathway kinases in patients with B cell malignancies," said Matthew Davids, MD, MMSc, Associate Director of the Center for Chronic Lymphocytic Leukemia at Dana-Farber. Dr. Davids continued, "We are particularly encouraged by the depth of response in the CLL patients, which compares favorably to historical data for ibrutinib monotherapy in this relapsed population. Our data support further exploration of dual BCR pathway blockade in CLL and other B cell malignancies."

Michael S. Weiss, the Company’s Executive Chairman and Chief Executive Officer, stated "We want to thank Dr. Davids and the team at Dana-Farber, and most importantly the patients who participated in this trial. We are excited to publish the first ever data evaluating the all oral combination of a PI3K delta inhibitor with a BTK inhibitor and believe this paper further highlights the favorable safety profile and combinability of umbralisib as compared to prior generation PI3k deltas. We believe these data support our plans to develop combinations utilizing umbralisib plus our BTK inhibitor, TG-1701, which has already demonstrated activity in patients in early clinical studies."

On December 17, 2018 Bristol-Myers Squibb Company (NYSE:BMY) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has recommended the expanded approval of Sprycel (dasatinib), in combination with chemotherapy, to include the treatment of pediatric patients with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) (Press release, Bristol-Myers Squibb, DEC 17, 2018, View Source [SID1234532093]). The positive opinion includes the tablet form of Sprycel and the powder for oral suspension formulation, which was first approved by the European Commission (EC) in July 2018, making Sprycel the only tyrosine kinase inhibitor with a formulation developed for administration in pediatric patients and patients who cannot swallow tablets. The CHMP recommendation will now be reviewed by the EC, which has the authority to approve medicines for the European Union (EU).

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"We are pleased with today’s CHMP recommendation for Sprycel in pediatric patients with Ph+ ALL, and look forward to the possibility of expanding Sprycel’s pediatric indications in the EU to include young patients with this particularly high-risk leukemia," said Fouad Namouni, M.D., head, oncology development, Bristol-Myers Squibb.

The application is based on data from CA180-372 (NCT01460160), an ongoing Phase 2 trial evaluating the addition of Sprycel to a chemotherapy regimen modeled on a Berlin-Frankfurt-Munster high-risk backbone in pediatric patients with newly diagnosed Ph+ ALL.

About Sprycel

Sprycel first received FDA approval in 2006 for the treatment of adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP) who are resistant or intolerant to prior therapy including imatinib. At that time, Sprycel also received FDA approval for adults with Ph+ acute lymphoblastic leukemia (ALL) who are resistant or intolerant to prior therapy. Sprycel is approved and marketed for these indications in more than 60 countries.

Sprycel is also an FDA-approved treatment for adults with newly diagnosed Ph+ CML-CP and is approved for this indication in more than 50 countries.

Both the FDA and the European Commission approved the expansion of Sprycel’s indication to include pediatric patients with Ph+ CML-CP in November 2017 and July 2018.

U.S. FDA-APPROVED INDICATIONS FOR SPRYCEL

SPRYCEL (dasatinib) is indicated for the treatment of adults with:

Newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase
Chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy
SPRYCEL is indicated for the treatment of pediatric patients with:

Ph+ CML in chronic phase
IMPORTANT SAFETY INFORMATION

Myelosuppression

Treatment with SPRYCEL is associated with severe (NCI CTCAE Grade 3/4) thrombocytopenia, neutropenia, and anemia, which occur earlier and more frequently in patients with advanced phase CML or Ph+ ALL than in patients with chronic phase CML. Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities.

In patients with chronic phase CML, perform complete blood counts (CBCs) every 2 weeks for 12 weeks, then every 3 months thereafter, or as clinically indicated
In patients with advanced phase CML or Ph+ ALL, perform CBCs weekly for the first 2 months and then monthly thereafter, or as clinically indicated
Myelosuppression is generally reversible and usually managed by withholding SPRYCEL temporarily and/or dose reduction
In clinical studies, myelosuppression may have also been managed by discontinuation of study therapy
Hematopoietic growth factor has been used in patients with resistant myelosuppression
Bleeding-Related Events

SPRYCEL can cause serious and fatal bleeding. In all CML or Ph+ ALL clinical studies, Grade ≥3 central nervous system (CNS) hemorrhages, including fatalities, occurred in <1% of patients receiving SPRYCEL. The incidence of Grade 3/4 hemorrhage, occurred in 5.8% of adult patients and generally required treatment interruptions and transfusions. The incidence of Grade 5 hemorrhage occurred in 0.4% of adult patients. The most frequent site of hemorrhage was gastrointestinal.

Most bleeding events in clinical studies were associated with severe thrombocytopenia
In addition to causing thrombocytopenia in human subjects, dasatinib caused platelet dysfunction in vitro
Concomitant medications that inhibit platelet function or anticoagulants may increase the risk of hemorrhage
Fluid Retention

SPRYCEL may cause fluid retention. After 5 years of follow-up in the adult randomized newly diagnosed chronic phase CML study (n=258), grade 3/4 fluid retention was reported in 5% of patients, including 3% of patients with grade 3/4 pleural effusion. In adult patients with newly diagnosed or imatinib resistant or intolerant chronic phase CML, grade 3/4 fluid retention occurred in 6% of patients treated with SPRYCEL at the recommended dose (n=548). In adult patients with advanced phase CML or Ph+ ALL treated with SPRYCEL at the recommended dose (n=304), grade 3/4 fluid retention was reported in 8% of patients, including grade 3/4 pleural effusion reported in 7% of patients. In pediatric patients with chronic phase CML cases of Grade 1 or 2 fluid retention were reported in 10.3% of patients.

Patients who develop symptoms of pleural effusion or other fluid retention, such as new or worsened dyspnea on exertion or at rest, pleuritic chest pain, or dry cough should be evaluated promptly with a chest x-ray or additional diagnostic imaging as appropriate
Fluid retention events were typically managed by supportive care measures that may include diuretics or short courses of steroids
Severe pleural effusion may require thoracentesis and oxygen therapy
Consider dose reduction or treatment interruption
Cardiovascular Events

SPRYCEL can cause cardiac dysfunction. After 5 years of follow-up in the randomized newly diagnosed chronic phase CML trial in adults (n=258), the following cardiac adverse reactions occurred:

Cardiac ischemic events (3.9% dasatinib vs 1.6% imatinib), cardiac related fluid retention (8.5% dasatinib vs 3.9% imatinib), and conduction system abnormalities, most commonly arrhythmia and palpitations (7.0% dasatinib vs 5.0% imatinib). Two cases (0.8%) of peripheral arterial occlusive disease occurred with imatinib and 2 (0.8%) transient ischemic attacks occurred with dasatinib
Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately.

Pulmonary Arterial Hypertension (PAH)

SPRYCEL may increase the risk of developing PAH in adult and pediatric patients, which may occur any time after initiation, including after more than 1 year of treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention. PAH may be reversible on discontinuation of SPRYCEL.

Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating SPRYCEL and during treatment. If PAH is confirmed, SPRYCEL should be permanently discontinued
QT Prolongation

SPRYCEL may increase the risk of prolongation of QTc in patients including those with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking antiarrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy

Correct hypokalemia or hypomagnesemia prior to and during SPRYCEL administration
Severe Dermatologic Reactions

Cases of severe mucocutaneous dermatologic reactions, including Stevens-Johnson syndrome and erythema multiforme, have been reported in patients treated with SPRYCEL.

Discontinue permanently in patients who experience a severe mucocutaneous reaction during treatment if no other etiology can be identified
Tumor Lysis Syndrome (TLS)

TLS has been reported in patients with resistance to prior imatinib therapy, primarily in advanced phase disease.

Due to potential for TLS, maintain adequate hydration, correct uric acid levels prior to initiating therapy with SPRYCEL, and monitor electrolyte levels
Patients with advanced stage disease and/or high tumor burden may be at increased risk and should be monitored more frequently
Embryo-Fetal Toxicity

Based on limited human data, SPRYCEL can cause fetal harm when administered to a pregnant woman. Hydrops fetalis, fetal leukopenia and fetal thrombocytopenia have been reported with maternal exposure to SPRYCEL. Transplacental transfer of dasatinib has been measured in fetal plasma and amniotic fluid at concentrations comparable to those in maternal plasma.

Advise females of reproductive potential to avoid pregnancy, which may include the use of effective contraception, during treatment with SPRYCEL and for 30 days after the final dose
Effects on Growth and Development in Pediatric Patients

In pediatric trials of SPRYCEL in chronic phase CML after at least 2 years of treatment, adverse reactions associated with bone growth and development were reported in 5 (5.2%) patients, one of which was severe in intensity (Growth Retardation Grade 3). These 5 cases included cases of epiphyses delayed fusion, osteopenia, growth retardation, and gynecomastia. Of these 5 cases, 1 case of osteopenia and 1 case of gynecomastia resolved during treatment.

Lactation

No data are available regarding the presence of dasatinib in human milk, the effects of the drug on the breastfed child or the effects of the drug on milk production. However, dasatinib is present in the milk of lactating rats.

Because of the potential for serious adverse reactions in nursing children from SPRYCEL, breastfeeding is not recommended during treatment with SPRYCEL and for 2 weeks after the final dose
Drug Interactions

Strong CYP3A4 inhibitors: The coadministration with strong CYP3A inhibitors may increase dasatinib concentrations. Increased dasatinib concentrations may increase the risk of toxicity. Avoid concomitant use of strong CYP3A4 inhibitors. If concomitant administration of a strong CYP3A4 inhibitor cannot be avoided, consider a SPRYCEL dose reduction
Grapefruit juice may increase plasma concentrations of SPRYCEL and should be avoided
Strong CYP3A4 inducers: The coadministration of SPRYCEL with strong CYP3A inducers may decrease dasatinib concentrations. Decreased dasatinib concentrations may reduce efficacy. Consider alternative drugs with less enzyme induction potential. If concomitant administration of a strong CYP3A4 inducer cannot be avoided, consider a SPRYCEL dose increase
St. John’s wort may decrease plasma concentrations of SPRYCEL and should be avoided
Gastric Acid Reducing Agents: The coadministration of SPRYCEL with a gastric acid reducing agent may decrease the concentrations of dasatinib. Decreased dasatinib concentrations may reduce efficacy.

Do not administer H2 antagonists or proton pump inhibitors with SPRYCEL. Consider the use of antacids in place of H2 antagonists or proton pump inhibitors. Administer the antacid at least 2 hours prior to or 2 hours after the dose of SPRYCEL. Avoid simultaneous administration of SPRYCEL with antacids.
Adverse Reactions

The safety data reflects exposure to SPRYCEL at all doses tested in clinical studies (n=2809) including 324 adult patients with newly diagnosed chronic phase CML, 2388 adult patients with imatinib resistant or intolerant chronic or advanced phase CML or Ph+ ALL, and 97 pediatric patients with chronic phase CML.

The median duration of therapy in a total of 2712 SPRYCEL-treated adult patients was 19.2 months (range 0–93.2 months). Median duration of therapy in:

1618 adult patients with chronic phase CML was 29 months (range 0–92.9 months)
Median duration for 324 adult patients in the newly diagnosed chronic phase CML trial was approximately 60 months
1094 adult patients with advanced phase CML or Ph+ ALL was 6.2 months (range 0–93.2 months)
In two non-randomized trials in 97 pediatric patients with chronic phase CML (51 patients newly diagnosed and 46 patients resistant or intolerant to previous treatment with imatinib), the median duration of therapy was 51.1 months (range 1.9 to 99.6 months).

In the newly diagnosed adult chronic phase CML trial, after a minimum of 60 months of follow-up, the cumulative discontinuation rate for 258 patients was 39%.

In the overall population of 2712 adult SPRYCEL-treated patients, 88% of patients experienced adverse reactions at some time and 19% experienced adverse reactions leading to treatment discontinuation.

Among the 1618 adult SPRYCEL-treated patients with chronic phase CML, drug-related adverse reactions leading to discontinuation were reported in 329 (20.3%) patients.

In the adult newly diagnosed chronic phase CML trial, drug was discontinued for adverse reactions in 16% of SPRYCEL-treated patients with a minimum of 60 months of follow-up
Among the 1094 SPRYCEL-treated patients with advanced phase CML or Ph+ ALL, drug-related adverse reactions leading to discontinuation were reported in 191 (17.5%) patients.

Among the 97 pediatric subjects, drug-related adverse reactions leading to discontinuation were reported in 1 patient (1%).

Patients ≥65 years are more likely to experience the commonly reported adverse reactions of fatigue, pleural effusion, diarrhea, dyspnea, cough, lower gastrointestinal hemorrhage, and appetite disturbance, and more likely to experience the less frequently reported adverse reactions of abdominal distention, dizziness, pericardial effusion, congestive heart failure, hypertension, pulmonary edema and weight decrease, and should be monitored closely.

In adult newly diagnosed chronic phase CML patients:
Drug-related serious adverse reactions (SARs) were reported for 16.7% of patients. Serious adverse reactions reported in ≥5% of patients included pleural effusion (5%)
Grade 3/4 laboratory abnormalities included neutropenia (29%), thrombocytopenia (22%), anemia (13%), hypophosphatemia (7%), hypocalcemia (4%), elevated bilirubin (1%), and elevated creatinine (1%)
In adult patients resistant or intolerant to prior imatinib therapy:
Drug-related SARs were reported for 26.1% of SPRYCEL-treated patients treated at the recommended dose of 100 mg once daily in the randomized dose-optimization trial of patients with chronic phase CML resistant or intolerant to prior imatinib therapy. Serious adverse reactions reported in ≥5% of patients included pleural effusion (10%)
Grade 3/4 hematologic laboratory abnormalities in chronic phase CML patients resistant or intolerant to prior imatinib therapy who received SPRYCEL 100 mg once daily with a minimum follow up of 60 months included neutropenia (36%), thrombocytopenia (24%), and anemia (13%). Other grade 3/4 laboratory abnormalities included: hypophosphatemia (10%), and hypokalemia (2%)
Among chronic phase CML patients with resistance or intolerance to prior imatinib therapy, cumulative grade 3/4 cytopenias were similar at 2 and 5 years including: neutropenia (36% vs 36%), thrombocytopenia (23% vs 24%), and anemia (13% vs 13%)
Grade 3/4 elevations of transaminases or bilirubin and Grade 3/4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases of CML
Elevations in transaminases or bilirubin were usually managed with dose reduction or interruption
Patients developing Grade 3/4 hypocalcemia during the course of SPRYCEL therapy often had recovery with oral calcium supplementation
In pediatric subjects with Ph+ CML in chronic phase
Drug-related SARs were reported for 14.4% of pediatric patients
In the pediatric studies, the rates of laboratory abnormalities were consistent with the known profile for laboratory parameters in adults
Most common adverse reactions (≥15%) in patients included myelosuppression, fluid retention events, diarrhea, headache, skin rash, hemorrhage, dyspnea, fatigue, nausea, and musculoskeletal pain