Gamida Cell Announces Data for Omidubicel Presented at the International Society for Cellular and Gene Therapy 2019 Annual Meeting

On May 31, 2019 Gamida Cell Ltd. (Nasdaq: GMDA), a leading cellular and immune therapeutics company, reported that two presentations on omidubicel1 (formerly known as NiCord), an investigational advanced cell therapy in Phase 3 clinical development designed to enhance the life-saving benefits of hematopoietic stem cell (bone marrow) transplant, took place at the International Society for Cell and Gene Therapy (ISCT) 2019 Annual Meeting being held in Melbourne, Australia (Press release, Gamida Cell, MAY 31, 2019, Gamida Cell Announces Data for Omidubicel Presented at the International Society for Cellular and Gene Therapy 2019 Annual Meeting
[SID1234536776]). The presentations included a summary of clinical and translational data from the completed Phase 1/2 clinical study of omidubicel in patients with high-risk hematologic malignancies, or blood cancers. Results from the Phase 1/2 study showed that patients transplanted with omidubicel had rapid and durable engraftment of neutrophils and platelets, as well as prompt immune reconstitution. An international, randomized Phase 3 study of omidubicel in patients with hematologic malignancies is currently ongoing.2

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"In the Phase 1/2 clinical study, patients who received omidubicel had a clinically meaningful reduction in their time to neutrophil and platelet recovery compared to a real-world cohort of patients who received a standard umbilical cord blood transplant. The neutrophil recovery observed with omidubicel also resulted in fewer days spent in the hospital compared to the comparator cohort," said Joanne Kurtzberg, M.D., Director of the Marcus Center for Cellular Cures and the Carolinas Cord Blood Bank at Duke University Medical Center. "These data suggest an important potential step toward making stem cell transplantation safer and more accessible to patients with lethal blood cancers, and I am pleased to be participating in the Phase 3 study currently enrolling patients."

Despite the curative potential of bone marrow transplants, it is estimated that more than 40 percent of eligible patients in the U.S. do not receive one for various reasons, including finding a matched donor.3 Even for patients who do receive a transplant, treatment is not always effective and can lead to serious complications that can dramatically affect quality of life.4 Omidubicel is intended to address the current limitations of bone marrow transplant by providing a therapeutic dose of cells while preserving the cells’ functional therapeutic characteristics.

"At Gamida Cell, our aspiration is to bring the first FDA-approved cell therapy for bone marrow transplantation to patients," stated Ronit Simantov, M.D., chief medical officer at Gamida Cell. "These data demonstrate the potential of omidubicel to give patients with high-risk blood cancers, particularly those who would not otherwise receive a bone marrow transplant from a matched donor, an opportunity for a cure."

Data Presented at ISCT 2019 Annual Meeting

Phase 1/2 Clinical Data

The presentation, "NiCord, an Expanded Cord Blood Product, Accelerates Engraftment After Myeloablative Conditioning," described results from the completed multicenter, Phase 1/2 clinical trial of omidubicel in 36 patients with high-risk hematologic malignancies and no readily available matched sibling or matched unrelated adult donor. The key primary endpoint was the cumulative incidence of neutrophil engraftment at 42 days. Additionally, the omidubicel patient cohort was compared to a retrospective cohort of patients who received standard cord blood transplant using data from the Center for International Blood and Marrow Transplant Research (CIBMTR).

Data from the study demonstrated that patients transplanted with omidubicel had rapid and durable engraftment of neutrophils and platelets. The age-adjusted cumulative incidence of neutrophil engraftment at 42 days following transplantation was 94 percent for omidubicel recipients compared to 85 percent for the CIBMTR cohort. Among patients who engrafted, the median time to neutrophil recovery was 11.5 days (95 percent confidence interval (CI): 9-14 days) for omidubicel recipients compared to 21 days (95 percent CI: 20-23 days) for the CIBMTR cohort (p < 0.001). For patients achieving platelet recovery, the median time to platelet recovery was 34 days (95 percent CI: 32-42 days) and 46 days (95 percent CI: 42-50 days) for the omidubicel and CIBMTR cohorts, respectively (p < 0.001). Omidubicel demonstrated an acceptable safety profile, with hypertension reported as the most common adverse event attributable to omidubicel infusion, and moderate to severe chronic graft vs. host disease reported in 9.8 percent of patients at one year following transplantation. Primary hospital discharge occurred at a median of 20 days following transplantation. Omidubicel recipients spent a median of 73 days alive and out of hospital during the first 100 days following transplantation.

Phase 1/2 Translational Data

The presentation, "Rapid and Robust CD4+ and CD8+ T-, NK-, B- and Monocyte Reconstitution after Nicotinamide-Expanded Cord Blood Transplantation," described in-depth immune reconstitution data from the completed Phase 1/2 clinical study of omidubicel. Immune reconstitution for 27 patients receiving omidubicel was compared to retrospective cohorts of adolescent and young adults with hematologic malignancies receiving unmanipulated cord blood transplantation (unCBT, n = 27) or unrelated bone marrow transplantation (BMT, n =20). The primary endpoint was the probability of achieving CD4+ immune reconstitution (> 50×106/L) within the first 100 days. Secondary endpoints included the recovery of B cells, CD4+ T cells and natural killer (NK) cells during the first year after transplantation. Analyses were performed at the University Medical Centre Utrecht, Laboratory of Translational Immunology.

The analysis showed that 91 percent of patients receiving omidubicel achieved successful immune reconstitution of CD4+ T cells at 100 days after transplantation. Reconstitution of T cells in the omidubicel group (median age 41.5 years) was similar to the unCBT and BMT cohorts (median age 15.4 and 14.3 years, respectively), despite the younger age of the cohorts, who would be expected to reconstitute faster. In addition, reconstitution of a number of cell types, including B cells (p = 0.026) and NK cells (p < 0.001), was significantly faster after transplantation with omidubicel compared to the cohorts, and suggests that omidubicel reconstitutes diverse functions of the immune system.

About Omidubicel

Omidubicel (formerly known as NiCord), the company’s lead clinical program, is an advanced cell therapy under development as a potential life-saving allogeneic hematopoietic stem cell (bone marrow) transplant solution for patients with hematologic malignancies (blood cancers).1 Omidubicel is the first bone marrow transplant product to receive Breakthrough Therapy Designation from the U.S. Food and Drug Administration and has also received Orphan Drug Designation in the U.S. and EU. In a Phase 1/2 clinical study, omidubicel demonstrated rapid and durable time to engraftment and was generally well-tolerated.5 A Phase 3 study evaluating omidubicel in patients with leukemia and lymphoma is ongoing in the U.S., Europe and Asia.2 Omidubicel is also being evaluated in a Phase 1/2 clinical study in patients with severe aplastic anemia.6 The aplastic anemia investigational new drug application is currently filed with the FDA under the brand name CordIn, which is the same investigational development candidate as omidubicel. For more information on clinical trials of omidubicel, please visit www.clinicaltrials.gov.

Omidubicel is an investigational therapy, and its safety and efficacy has not been evaluated by the U.S. Food and Drug Administration or any other health authority.

Turning Point Therapeutics Announces Updated Interim Clinical Data of Repotrectinib in Advanced ROS1+ Non-Small Cell Lung Cancer

On May 31, 2019 Turning Point Therapeutics, Inc. (NASDAQ: TPTX), a precision oncology company developing novel drugs to address treatment resistance, reported updated interim data from its ongoing Phase 1/2 TRIDENT-1 clinical study of lead drug candidate repotrectinib in ROS1-positive non-small cell lung cancer (NSCLC) patients (Press release, Turning Point Therapeutics, MAY 31, 2019, View Source [SID1234536729]).

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The results, which will be presented today during an oral session at the annual meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), demonstrate ongoing antitumor activity and a manageable safety profile across multiple dose cohorts in both tyrosine kinase inhibitor (TKI) naïve and TKI-pretreated patients, including patients with intracranial disease.

"With additional follow up and new patients enrolled in the TRIDENT-1 study, repotrectinib continues to demonstrate promising efficacy and a safety profile consistent with a potential best-in-class ROS1 therapy for patients with advanced non-small cell lung cancer," said Dr. Byoung Chul Cho, Yonsei Cancer Center at Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea. "The ongoing Phase 1 data remain encouraging in both TKI-naïve patients with intracranial disease and patients pretreated with crizotinib — including those with difficult to treat solvent front mutations — where there are currently very few therapeutic options."

Dr. Cho is an investigator for the TRIDENT-1 study and will present the data today at the annual ASCO (Free ASCO Whitepaper) conference.

Repotrectinib is an investigational next-generation TKI designed to effectively target ROS1 and TRK A/B/C and systemically overcome resistant mutations that invariably result following treatment with other TKIs. ROS1 rearrangement is an oncogenic driver of tumors in up to 2.6 percent of U.S. advanced NSCLC patients.

As of the March 4, 2019 data cut-off, the interim Phase 1 data showed the following results.

Preliminary Safety Analysis (n=83):

A total of 83 (ROS1+, NTRK+ and ALK+) patients were treated with repotrectinib at dose levels from 40 mg daily (QD) to 200 mg twice daily (BID).
Repotrectinib was generally well tolerated, with the most frequent treatment emergent adverse events (TEAEs) being Grade 1 or 2. The TEAEs found in >25% of pts were dizziness (57%), dysgeusia (51%), dyspnea (30%), fatigue (30%), constipation (29%), paresthesia (29%), and anemia (28%). There were few Grade 3 treatment-related AEs (anemia (n=3); dizziness (n=2); and dyspnea, hypophosphatemia, hypoxia, pleural effusion, and weight increase (all n=1)), and no Grade 4 treatment-related AEs or cases of dizziness leading to treatment discontinuation.
No additional dose-limiting toxicities (DLTs) have occurred since the last data cut-off of Oct. 31, 2018. Prior DLTs included Grade 3 dyspnea/hypoxia (n=1), and Grade 2 (n=1) and Grade 3 (n=2) dizziness. Four total Grade 5 TEAEs (one of four determined to be possibly treatment related) have occurred, with one Grade 5 case of respiratory failure reported as related to disease progression since the last interim data update.
Preliminary Efficacy Analysis (n=33)

Within the ROS1+ NSCLC blinded independent central review (BICR) efficacy evaluable population (n=33), the median number of prior TKI therapies was one (range 0 to 3), the majority of which were crizotinib.
Forty-five percent of patients remained on treatment (15/33), with 12 of the 15 (80%) patients remaining on treatment for more than 12 months.
TKI-Naïve Efficacy Analysis

In TKI-naïve patients, overall response rate (ORR) by BICR was 82 percent (9/11). At a dose of 160 mg QD or above, the likely recommended Phase 2 dose, ORR by BICR remains at 83 percent, consistent with the prior update. Efficacy results are summarized in the following table:

Prior Interim Analysis by BICR
Oct. 31, 2018 Data cut-off Current Interim Analysis by BICR
March 4, 2019 Data cut-off
All ROS1 NSCLC (TKI
Naïve & Pretreated) N=28 N=33
TKI Naïve N=10 N=11
Median Follow up –
(Range) 16.4 months
(5.3-16.6+) 16.4 months
(3.5+-19.4+)
ORR (%)
(95% CI) 9/10 (90)
(56-100) 9/11 (82)
(48-98)
ORR at 160 mg QD or
above 5/6 (83) 5/6 (83)
Median Duration of
Response – Months
(Range) Not Reached
(5.5+-14.9+)
5 of 9 remain in cPR
(5.5+ to 14.9+ months) Not Reached
(5.6-17.7+)
5 of 9 remain in cPR (10.9+ to 17.7+ months)
Intracranial ORR n (%)
(95% CI) 3/3 (100)
(29-100) 3/3 (100)
(29-100)
All remain in cPR
Clinical Benefit Rate (%)
(95% CI) 10/10 (100)
(69-100) 11/11 (100)
(72-100)
TKI-Pretreated Efficacy Analysis

In TKI-pretreated patients, ORR by BICR improved from 28 percent in the prior data cut-off to 32 percent, and from 44 percent to 55 percent in patients pretreated with 1 TKI and dosed at 160 mg QD or above. Efficacy results are summarized in the following table:

Prior Interim Analysis by BICR
Oct. 31, 2018 Data cut-off Current Interim Analysis by BICR
March 4, 2019 Data cut-off
All ROS1 NSCLC (TKI Naïve
& Pretreated) N=28 N=33
TKI Pretreated N=18 N=22
Median Follow up –
(Range) 12.9 months
(0.6-14.5) 14.6 months
(1.4-16.6+)
ORR (%)
(95% CI) 5/18 (28)
(10-53) 7/22 (32)
(14-55)

O
R
R

1 prior TKI 5/15 (33) 7/18 (39)
1 prior TKI
160 mg QD or above 4/9 (44) 6/11 (55)
1 prior TKI
crizotinib only
160 mg QD or above 3/6 (50) 4/7 (57)
2 or more prior TKIs 0/3 (0) 0/4 (0)
Duration of Response –
Months
# still in response (+) 1 of 5 responders still in cPR at 1.9+ months 3 of 7 responders still in cPR at 1.0+ to 7.6+ months
ORR in G2032R Solvent
Front Mutations
(%) 1/4 (25) 2/5 (40)
Intracranial ORR n (%)
1 prior TKI 2/4 (50)
2/3 (67) 3/5 (60)
3/4 (75)
Clinical Benefit Rate (%)
(95% CI) 14/18 (78)
(52-94) 16/22 (73)
(50-89)
Five patients pretreated with crizotinib had a ROS1 G2032R solvent front mutation detected at baseline by plasma cfDNA or next-generation sequencing tests. All five patients had tumor regressions, including two confirmed partial responses (cPR) at the 160 mg QD dose level.

"Since first reporting preliminary TRIDENT-1 interim data for repotrectinib at the 2018 annual ASCO (Free ASCO Whitepaper) meeting, we are very pleased to see the results continue to strengthen with each subsequent data cut-off while maintaining a consistent safety profile in both TKI-naïve and TKI-pretreated ROS1+ NSCLC patients," said Athena Countouriotis, M.D., president and chief executive officer. "The current treatment options for patients with ROS1+ advanced non-small cell lung cancer are limited, particularly when resistance develops to other TKIs. We look forward to finalizing our recommended Phase 2 dose and beginning the registrational portion of TRIDENT-1 in the second half of this year."

Financial Update
The company separately filed its Form 10-Q today for the first quarter of 2019. Operating expenses during the first quarter were $14.1 million compared to $4.9 million in the first quarter of 2018. The $9.2 million increase was primarily due to increased personnel expenses and activities for the development of repotrectinib, TPX-0022 and TPX-0046. Net cash used in operating activities was $10.2 million, an increase from $5.4 million in the prior-year period.

Turning Point expects expenses will increase through the year as it plans to initiate up to four clinical trials in 2019 including: the Phase 2 TRIDENT-1 registrational study for repotrectinib; a Phase 1/2 study of repotrectinib in pediatric patients with advanced solid tumors with NTRK, ALK, or ROS1 alterations; a Phase 1 dose-finding study for TPX-0022, a novel MET, CSF1R and SRC inhibitor in patients with advanced solid tumors harboring genetic alterations in MET; and, pending completion of IND-enabling studies, a Phase 1 study of TPX-0046, a novel RET and SRC inhibitor in patients with advanced solid tumors with oncogenic RET genetic alterations.

Cash and cash equivalents at March 31 were $90 million. In addition, the company raised net proceeds of $175.2 million from its April 2019 initial public offering. The company projects its cash position will be sufficient to fund current operations into the second half of 2021.

Ultragenyx to Present at Upcoming Investor Conferences

On May 31, 2019 Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE), a biopharmaceutical company focused on the development of novel products for serious rare and ultra-rare genetic diseases, reported that it will present at the following upcoming investor conferences (Press release, Ultragenyx Pharmaceutical, MAY 31, 2019, View Source [SID1234536730]):

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Shalini Sharp, the company’s Chief Financial Officer, will present at the Jefferies Healthcare Conference on Tuesday, June 4, 2019 at 8:00 a.m. ET in New York, NY.

Emil D. Kakkis, M.D., Ph.D., the company’s Chief Executive Officer, President and Founder, will present at the Goldman Sachs 40TH Annual Global Healthcare Conference on Thursday, June 13, 2019 at 9:20 a.m. PT in Palos Verdes, CA.
The live and archived webcast of the company presentations will be accessible from the company’s website at View Source The replay of the webcast will be available for 90 days.

Hengrui Medicine’s PD-1 Drug Approved in China for Lymphoma

On May 31, 2019 Jiangsu Hengrui Medicine reported China regulators approved its PD-1 drug, camrelizumab, as a third-line treatment for recurrent or refractory classical Hodgkin’s lymphoma (Press release, ChinaBio, MAY 31, 2019, View Source [SID1234556331]). Camrelizumab is the third domestic PD-1/PD-L1 drug approved in China; previously, Junshi’s Tuoyi and Innovent’s Tyvyx were granted marketing approvals. Two US-based companies have also entered China’s PD-1/PD-L1 market — Merck with Keytruda (also for melanoma) and Bristol Myers Squibb with Opdivo. Hengrui said it is testing camrelizumab in about 20 China clinical trials.

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U.S. FDA Approves Supplemental New Drug Application Adding Overall Survival Data for XOSPATA® (gilteritinib)

On May 30, 2019 Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D. "Astellas") reported that the U.S. Food and Drug Administration (FDA) approved a supplemental New Drug Application (sNDA) to update the U.S. product labeling for XOSPATA (gilteritinib) to include final analysis data from the ADMIRAL trial (Press release, Astellas Pharma, MAY 30, 2019, View Source [SID1234536678]). The data demonstrated improvement in Overall Survival in those treated with gilteritinib monotherapy versus salvage chemotherapy in adult patients with relapsed (disease that has returned) or refractory (resistant to treatment) Acute Myeloid Leukemia (AML) with an FMS-like tyrosine kinase 3 (FLT3) mutation.

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"The ADMIRAL trial’s Overall Survival (OS) findings are encouraging for patients and families impacted by relapsed/refractory FLT3 mutation-positive AML," said Alexander Perl, M.D., Abramson Cancer Center, University of Pennsylvania. "The data underscore the importance of single-agent XOSPATA for this patient population that, until recently, had few remaining treatment options."

Results from the ADMIRAL trial show the median OS for patients who received XOSPATA was 9.3 months compared to 5.6 months for patients who received salvage chemotherapy (Hazard Ratio = 0.64 (95% CI 0.49, 0.83), P=0.0004). The other co-primary endpoints of Complete Remission (CR)/Complete Remission with Partial Hematologic Recovery (CRh) in the XOSPATA arm at the interim analysis was 21% (95% CI: 14.5, 28.8).1

The safety profile of XOSPATA is based on 319 patients with relapsed or refractory AML in three clinical trials (NCT02421939, NCT02014558, and NCT02181660). Fatal adverse reactions occurred in 2% of patients receiving XOSPATA. These included cardiac arrest (1%) and one case each of differentiation syndrome and pancreatitis. The most frequent (≥5%) nonhematological serious adverse reactions reported in patients were fever (13%), dyspnea (9%), renal impairment (8%), transaminase increased (6%) and noninfectious diarrhea (5%). The most frequent (≥5%) grade ≥3 nonhematological adverse reactions reported in patients were transaminase increased (21%), dyspnea (12%), hypotension (7%), mucositis (7%), myalgia/arthralgia (7%), and fatigue/malaise (6%).

Please see Important Safety Information including BOXED WARNING at the end of this press release.

"Delivering innovation and value to address the unmet medical needs of patients is at the core of everything we do," said Bernhardt G. Zeiher, M.D., Chief Medical Officer, Astellas. "The FDA’s approval of the sNDA based on Overall Survival data further highlights the strong potential XOSPATA has to help patients suffering from FLT3 mutation-positive AML, a life-threatening disease."

The initial approval of XOSPATA in November 2018 by the FDA was based on an interim analysis of the following endpoints in the ADMIRAL clinical trial: the rate of complete remission (CR)/complete remission with partial hematologic recovery (CRh); the duration of CR/CRh (DOR); and the rate of conversion from transfusion dependence to transfusion independence.

The FDA reviewed the sNDA for XOSPATA under the Oncology Center of Excellence Real-Time Oncology Review pilot program, which aims to explore a more efficient review process by allowing the FDA to evaluate clinical data as soon as trial results become available.

XOSPATA was discovered through a research collaboration with Kotobuki Pharmaceutical Co., Ltd., and Astellas has exclusive global rights to develop, manufacture and commercialize XOSPATA.

XOSPATA was approved by the Japan Ministry of Health, Labor and Welfare (MHLW) for relapsed or refractory AML with FLT3 mutations and launched as XOSPATA 40 mg Tablets in 2018.2 In February 2019, the European Medicines Agency accepted a marketing authorization application (MAA) for regulatory review. The MAA is for the oral once-daily therapy XOSPATA for the treatment of adult patients who have relapsed or refractory AML with a FLT3 mutation.3

Astellas is currently investigating gilteritinib in various FLT3 mutation-positive AML patient populations through several Phase 3 trials. Visit View Source to learn more about ongoing gilteritinib clinical trials.

About the ADMIRAL Trial4
The Phase 3 ADMIRAL trial (NCT02421939) was an open-label, multicenter, randomized study of gilteritinib versus salvage chemotherapy in adult patients with FLT3 mutations who are refractory to, or have relapsed after, first-line AML therapy. The co-primary endpoints of the trial were Overall Survival and Complete Remission (CR)/Complete Remission with Partial Hematologic Recovery (CRh). The study enrolled 371 patients with relapsed or refractory AML and positive for FLT3 mutations present in bone marrow or whole blood. Subjects were randomized in a 2:1 ratio to receive gilteritinib (120 mg) or salvage chemotherapy.

About XOSPATA (gilteritinib)
XOSPATA is indicated for the treatment of adult patients who have relapsed or refractory Acute Myeloid Leukemia (AML) with an FMS-like tyrosine kinase 3 (FLT3) mutation as detected by an FDA-approved test.1

Important Safety Information

Contraindications
XOSPATA is contraindicated in patients with hypersensitivity to gilteritinib or any of the excipients. Anaphylactic reactions have been observed in clinical trials.

WARNING: DIFFERENTIATION SYNDROME

Patients treated with XOSPATA have experienced symptoms of differentiation syndrome, which can be fatal or life-threatening if not treated. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, or renal dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.

Warnings and Precautions

Differentiation Syndrome (See BOXED WARNING) 3% of 319 patients treated with XOSPATA in the clinical trials experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with XOSPATA included fever, dyspnea, pleural effusion, pericardial effusion, pulmonary edema, hypotension, rapid weight gain, peripheral edema, rash, and renal dysfunction. Some cases had concomitant acute febrile neutrophilic dermatosis. Differentiation syndrome occurred as early as 2 days and up to 75 days after XOSPATA initiation and has been observed with or without concomitant leukocytosis. If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. Taper corticosteroids after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt XOSPATA until signs and symptoms are no longer severe.

Posterior Reversible Encephalopathy Syndrome (PRES) 1% of 319 patients treated with XOSPATA in the clinical trials experienced posterior reversible encephalopathy syndrome (PRES) with symptoms including seizure and altered mental status. Symptoms have resolved after discontinuation of XOSPATA. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). Discontinue XOSPATA in patients who develop PRES.

Prolonged QT Interval XOSPATA has been associated with prolonged cardiac ventricular repolarization (QT interval). 1% of the 317 patients with a post-baseline QTc measurement on treatment with XOSPATA in the clinical trial were found to have a QTc interval greater than 500 msec and 7% of patients had an increase from baseline QTc greater than 60 msec. Perform electrocardiogram (ECG) prior to initiation of treatment with XOSPATA, on days 8 and 15 of cycle 1, and prior to the start of the next two subsequent cycles. Interrupt and reduce XOSPATA dosage in patients who have a QTcF >500 msec. Hypokalemia or hypomagnesemia may increase the QT prolongation risk. Correct hypokalemia or hypomagnesemia prior to and during XOSPATA administration.

Pancreatitis 4% of 319 patients treated with XOSPATA in the clinical trials experienced pancreatitis. Evaluate patients who develop signs and symptoms of pancreatitis. Interrupt and reduce the dose of XOSPATA in patients who develop pancreatitis.

Embryo-Fetal Toxicity XOSPATA can cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with XOSPATA and for at least 6 months after the last dose of XOSPATA. Advise males with female partners of reproductive potential to use effective contraception during treatment with XOSPATA and for at least 4 months after the last dose of XOSPATA. Pregnant women, patients becoming pregnant while receiving XOSPATA or male patients with pregnant female partners should be apprised of the potential risk to the fetus.

Adverse Reactions

Fatal adverse reactions occurred in 2% of patients receiving XOSPATA. These were cardiac arrest (1%) and one case each of differentiation syndrome and pancreatitis. The most frequent (≥5%) nonhematological serious adverse reactions reported in patients were fever (13%), dyspnea (9%), renal impairment (8%), transaminase increased (6%) and noninfectious diarrhea (5%).

7% discontinued XOSPATA treatment permanently due to an adverse reaction. The most common (>1%) adverse reactions leading to discontinuation were aspartate aminotransferase increased (2%) and alanine aminotransferase increased (2%).

The most frequent (≥5%) grade ≥3 nonhematological adverse reactions reported in patients were transaminase increased (21%), dyspnea (12%), hypotension (7%), mucositis (7%), myalgia/arthralgia (7%), and fatigue/malaise (6%).

Other clinically significant adverse reactions occurring in ≤10% of patients included: electrocardiogram QT prolonged (9%), hypersensitivity (8%), pancreatitis (5%), cardiac failure (4%), pericardial effusion (4%), acute febrile neutrophilic dermatosis (3%), differentiation syndrome (3%), pericarditis/myocarditis (2%), large intestine perforation (1%), and posterior reversible encephalopathy syndrome (1%).

Lab Abnormalities Shifts to grades 3-4 nonhematologic laboratory abnormalities in XOSPATA treated patients included phosphate decreased (14%), alanine aminotransferase increased (13%), sodium decreased (12%), aspartate aminotransferase increased (10%), calcium decreased (6%), creatine kinase increased (6%), triglycerides increased (6%), creatinine increased (3%), and alkaline phosphatase increased (2%).

Drug Interactions
Combined P-gp and Strong CYP3A Inducers Concomitant use of XOSPATA with a combined P-gp and strong CYP3A inducer decreases XOSPATA exposure which may decrease XOSPATA efficacy. Avoid concomitant use of XOSPATA with combined P-gp and strong CYP3A inducers.

Strong CYP3A inhibitors Concomitant use of XOSPATA with a strong CYP3A inhibitor increases XOSPATA exposure. Consider alternative therapies that are not strong CYP3A inhibitors. If the concomitant use of these inhibitors is considered essential for the care of the patient, monitor patient more frequently for XOSPATA adverse reactions. Interrupt and reduce XOSPATA dosage in patients with serious or life-threatening toxicity.

Drugs that Target 5HT2B Receptor or Sigma Nonspecific Receptor Concomitant use of XOSPATA may reduce the effects of drugs that target the 5HT2B receptor or the sigma nonspecific receptor (e.g., escitalopram, fluoxetine, sertraline). Avoid concomitant use of these drugs with XOSPATA unless their use is considered essential for the care of the patient.

Specific Populations
Lactation: Advise women not to breastfeed during treatment with XOSPATA and for 2 months after the last dose.