SPRINT, an NCI-sponsored clinical study, represents a landmark in the treatment of NF1 PN1

SPRINT Phase II Stratum 1 was an open-label, multicenter, single-arm study coordinated with the National Cancer Institute. This study of 50 pediatric patients with NF1-related inoperable plexiform neurofibromas (PN) that caused significant morbidity was designed to assess the efficacy and safety of Koselugo in reducing the volume of NF1 PN.1,2

Sprint Phase ll Stratum1
Inclusion and Exclusion Criteria

The baseline characteristics of patients in SPRINT demonstrate the variability of NF1 PN1,2

Age

  • Median age of 10.2 years (range: 3.5 to 17.4 years)

Patients with and without past surgeries

  • 56% of patients had undergone at least 1 prior PN-related or NF1-related surgical procedure

Progressive and non-progressive PN

  • 42% of patients had a progressive PN (growth ≥20% in 12 to 15 months prior to enrollment)
  • 30% had a non-progressive PN

A range of PN volumes

  • 5.6 mL to 3820 mL target PN volume range (median 487.50 mL)

Koselugo is the first and only
FDA-approved treatment

for pediatric
patients ≥2 years, with NF1 and
symptomatic, inoperable PN2

REiNS GUIDELINES

The Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) Tumor Measurement Group was formed to develop standardized consensus recommendations for imaging response evaluation and endpoints in clinical trials for benign PN.3

Based on REiNS guidance, the SPRINT study was designed with:

  • The REiNS-recommended primary endpoint of ORR
  • Use of 3D MRI volumetric analysis to provide sensitive tumor response evaluation
  • Exploratory patient-reported outcomes to assess clinical benefit

NATURAL HISTORY OF NF1 PN: AN NCI-SPONSORED STUDY WHICH WAS NOT ASSOCIATED WITH THE SPRINT STUDY

NCI Natural History Study

The Natural History study of patients with NF1-related PN began enrollment in 2008 and is ongoing. NCI volumetric MRI assessments up to October 15, 2018 were transferred to AstraZeneca, to allow analysis of PN growth and progression-free survival of patients with NF1-related PN to serve as an external control for the SPRINT study. The following spider plot presents individual patient target PN volumes over 2.8 years1:

Percentage Change in  PN Volume
Percentage Change in  PN Volume

MECHANISM OF DISEASE AND MECHANISM OF ACTION

MECHANISM OF DISEASE4,5

Mechanism of Disease

MECHANISM OF ACTION2,5

Koselugo is a kinase inhibitor that blocks RAS pathway signaling by inhibiting MEK, downstream of RAS

Mechanism of Action
Mechanism of Disease & Mechanism of Action

*Pain intensity of the target PN was self-reported by patients ≥8 years of age using the NRS-11.

36 patients had evaluable pre-study volumetric MRI data. 28% (n=14) of patients had unknown PN progression status at baseline.

92 patients are presented in this plot for the Natural History study. The full Natural History analysis set includes all patients with NF1-related PN (all ages) who have at least 2 volumetric MRI scans. The age-matched cohort includes a subset of the full Natural History analysis set including patients with at least 2 volumetric MRI scans where the first scan done within the age range of 3 to 18 years was considered the baseline.

BSA=body surface area; ERK=extracellular signal-regulated kinase; MEK=mitogen-activated protein kinase kinase; MPNST=malignant peripheral nerve sheath tumor; MRI=magnetic resonance imaging; NCI=National Cancer Institute; NF1=neurofibromatosis type 1; NRS-11=Numeric Rating Scale 11; PN=plexiform neurofibromas; RAF=rapidly accelerated fibrosarcoma; RAS=rat sarcoma viral oncogene homolog; REiNS=Response Evaluation in Neurofibromatosis and Schwannomatosis.

IMPORTANT SAFETY INFORMATION

Cardiomyopathy. A decrease in left ventricular ejection fraction (LVEF) ≥10% below baseline occurred in 23% of 74 pediatric patients who received Koselugo in SPRINT. Four percent of patients experienced decreased LVEF below the institutional lower limit of normal (LLN). Grade 3 decreased LVEF occurred in one patient and resulted in dose reduction. All patients with decreased LVEF were asymptomatic and identified during routine echocardiography. Decreased LVEF resolved in 71% of these patients. Decreased LVEF resulting in permanent discontinuation of Koselugo occurred in a pediatric population with NF1 in an expanded access program. The safety of Koselugo has not been established in patients with a history of impaired LVEF or a baseline ejection fraction that is below the institutional LLN.

Assess ejection fraction by echocardiogram prior to initiating treatment, every 3 months during the first year of treatment, every 6 months thereafter, and as clinically indicated. Withhold, reduce dose, or permanently discontinue Koselugo based on severity of adverse reaction. In patients who interrupt Koselugo for decreased LVEF, obtain an echocardiogram or a cardiac MRI every 3 to 6 weeks. Upon resolution of decreased LVEF, obtain an echocardiogram or a cardiac MRI every 2 to 3 months.

Ocular Toxicity. Blurred vision, photophobia, cataracts, and ocular hypertension occurred in 15% of 74 pediatric patients receiving Koselugo in SPRINT. Blurred vision resulted in dose interruption in 2.7% of patients. Ocular toxicity resolved in 82% of 11 patients. Retinal pigment epithelial detachment (RPED) occurred in the pediatric population during treatment with single agent Koselugo and resulted in permanent discontinuation.

Conduct ophthalmic assessments prior to initiating Koselugo, at regular intervals during treatment, and for new or worsening visual changes. Permanently discontinue Koselugo in patients with retinal vein occlusion (RVO). Withhold Koselugo in patients with RPED, conduct ophthalmic assessments every 3 weeks until resolution, and resume Koselugo at a reduced dose. For other ocular toxicities, withhold, reduce dose, or permanently discontinue Koselugo based on severity of adverse reaction.

Gastrointestinal Toxicity. Diarrhea occurred in 77% of 74 pediatric patients who received Koselugo in SPRINT, including Grade 3 in 15% of patients. Diarrhea resulting in permanent discontinuation occurred in 1.4% of patients. Diarrhea resulting in dose interruption or dose reduction occurred in 15% and 1.4% of patients, respectively. The median time to first onset of diarrhea was 17 days, and the median duration was 2 days.

Advise patients to start an anti-diarrheal agent (eg, loperamide) and to increase fluid intake immediately after the first episode of diarrhea. Withhold, reduce dose, or permanently discontinue Koselugo based on severity of adverse reaction.

Skin Toxicity. Rash occurred in 91% of 74 pediatric patients who received Koselugo in SPRINT. The most frequent rashes included dermatitis acneiform (54%), maculopapular rash (39%), and eczema (28%). Grade 3 rash occurred in 8% of patients. Rash resulted in dose interruption in 11% of patients and dose reduction in 4% of patients. Monitor for severe skin rashes. Withhold, reduce dose, or permanently discontinue Koselugo based on severity of adverse reaction.

Increased Creatine Phosphokinase (CPK). Increased CPK occurred in 76% of 74 pediatric patients who received Koselugo in SPRINT, including Grade 3 or 4 in 9% of patients. Increased CPK resulted in dose reduction in 7% of patients. Increased CPK concurrent with myalgia occurred in 8% of patients, including one patient who permanently discontinued Koselugo for myalgia.

Obtain serum CPK prior to initiating Koselugo, periodically during treatment, and as clinically indicated. If increased CPK occurs, evaluate patients for rhabdomyolysis or other causes. Withhold, reduce dose, or permanently discontinue Koselugo based on severity of adverse reaction.

Increased Levels of Vitamin E and Risk of Bleeding. Koselugo capsules contain vitamin E (10 mg capsules contain 32 mg vitamin E as the excipient, D-alpha-tocopheryl polyethylene glycol 1000 succinate [TPGS], while Koselugo 25 mg capsules contain 36 mg vitamin E as TPGS). Vitamin E can inhibit platelet aggregation and antagonize vitamin K-dependent clotting factors. Daily vitamin E intake that exceeds the recommended or safe limits may increase the risk of bleeding. Supplemental vitamin E is not recommended if daily vitamin E intake (including the amount of vitamin E in Koselugo and supplement) will exceed the recommended or safe limits.

An increased risk of bleeding may occur in patients who are coadministered vitamin-K antagonists or anti-platelet antagonists with Koselugo. Monitor for bleeding in these patients and increase international normalized ratio (INR) monitoring in patients taking a vitamin-K antagonist. Perform anticoagulant assessments more frequently and adjust the dose of vitamin K antagonists or anti-platelet agents as appropriate.

Embryo-Fetal Toxicity. Based on findings from animal studies, Koselugo can cause fetal harm when administered to a pregnant woman. In animal studies, administration of selumetinib to mice during organogenesis caused reduced fetal weight, adverse structural defects, and effects on embryo-fetal survival at approximate exposures >5 times the human exposure at the clinical dose of 25 mg/m2 twice daily. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Koselugo and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Koselugo and for 1 week after the last dose.

Breastfeeding. Due to the potential for adverse reactions in a breastfed child, advise women not to breastfeed during treatment with Koselugo and for 1 week after the last dose.

Concomitant use of Koselugo with a strong or moderate CYP3A4 inhibitor or fluconazole increased selumetinib plasma concentrations, which may increase the risk of adverse reactions. Avoid coadministration of strong or moderate CYP3A4 inhibitors or fluconazole with Koselugo. If coadministration with strong or moderate CYP3A4 inhibitors or fluconazole cannot be avoided, reduce Koselugo dosage.

Concomitant use of Koselugo with a strong or moderate CYP3A4 inducer decreased selumetinib plasma concentrations, which may reduce Koselugo efficacy. Avoid concomitant use of strong or moderate CYP3A4 inducers with Koselugo.

The most common adverse reactions ≥40% are: vomiting, rash (all), abdominal pain, diarrhea, nausea, dry skin, musculoskeletal pain, fatigue, pyrexia, acneiform rash, stomatitis, headache, paronychia, and pruritus.

INDICATION

Koselugo is indicated for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN).


Please see complete Prescribing Information including Patient Information.

You may report side effects related to AstraZeneca products by clicking here.

IMPORTANT SAFETY INFORMATION

Cardiomyopathy. A decrease in left ventricular ejection fraction (LVEF) ≥10% below baseline occurred in 23% of 74 pediatric patients who received Koselugo in SPRINT. Four percent of patients experienced decreased LVEF below the institutional lower limit of normal (LLN). Grade 3 decreased LVEF occurred in one patient and resulted in dose reduction. All patients with decreased LVEF were asymptomatic and identified during routine echocardiography. Decreased LVEF resolved in 71% of these patients. Decreased LVEF resulting in permanent discontinuation of Koselugo occurred in a pediatric population with NF1 in an expanded access program. The safety of Koselugo has not been established in patients with a history of impaired LVEF or a baseline ejection fraction that is below the institutional LLN.

Assess ejection fraction by echocardiogram prior to initiating treatment, every 3 months during the first year of treatment, every 6 months thereafter, and as clinically indicated. Withhold, reduce dose, or permanently discontinue Koselugo based on severity of adverse reaction. In patients who interrupt Koselugo for decreased LVEF, obtain an echocardiogram or a cardiac MRI every 3 to 6 weeks. Upon resolution of decreased LVEF, obtain an echocardiogram or a cardiac MRI every 2 to 3 months.

Ocular Toxicity. Blurred vision, photophobia, cataracts, and ocular hypertension occurred in 15% of 74 pediatric patients receiving Koselugo in SPRINT. Blurred vision resulted in dose interruption in 2.7% of patients. Ocular toxicity resolved in 82% of 11 patients. Retinal pigment epithelial detachment (RPED) occurred in the pediatric population during treatment with single agent Koselugo and resulted in permanent discontinuation.

Conduct ophthalmic assessments prior to initiating Koselugo, at regular intervals during treatment, and for new or worsening visual changes. Permanently discontinue Koselugo in patients with retinal vein occlusion (RVO). Withhold Koselugo in patients with RPED, conduct ophthalmic assessments every 3 weeks until resolution, and resume Koselugo at a reduced dose. For other ocular toxicities, withhold, reduce dose, or permanently discontinue Koselugo based on severity of adverse reaction.

Gastrointestinal Toxicity. Diarrhea occurred in 77% of 74 pediatric patients who received Koselugo in SPRINT, including Grade 3 in 15% of patients. Diarrhea resulting in permanent discontinuation occurred in 1.4% of patients. Diarrhea resulting in dose interruption or dose reduction occurred in 15% and 1.4% of patients, respectively. The median time to first onset of diarrhea was 17 days, and the median duration was 2 days.

Advise patients to start an anti-diarrheal agent (eg, loperamide) and to increase fluid intake immediately after the first episode of diarrhea. Withhold, reduce dose, or permanently discontinue Koselugo based on severity of adverse reaction.

Skin Toxicity. Rash occurred in 91% of 74 pediatric patients who received Koselugo in SPRINT. The most frequent rashes included dermatitis acneiform (54%), maculopapular rash (39%), and eczema (28%). Grade 3 rash occurred in 8% of patients. Rash resulted in dose interruption in 11% of patients and dose reduction in 4% of patients. Monitor for severe skin rashes. Withhold, reduce dose, or permanently discontinue Koselugo based on severity of adverse reaction.

Increased Creatine Phosphokinase (CPK). Increased CPK occurred in 76% of 74 pediatric patients who received Koselugo in SPRINT, including Grade 3 or 4 in 9% of patients. Increased CPK resulted in dose reduction in 7% of patients. Increased CPK concurrent with myalgia occurred in 8% of patients, including one patient who permanently discontinued Koselugo for myalgia.

Obtain serum CPK prior to initiating Koselugo, periodically during treatment, and as clinically indicated. If increased CPK occurs, evaluate patients for rhabdomyolysis or other causes. Withhold, reduce dose, or permanently discontinue Koselugo based on severity of adverse reaction.

Increased Levels of Vitamin E and Risk of Bleeding. Koselugo capsules contain vitamin E (10 mg capsules contain 32 mg vitamin E as the excipient, D-alpha-tocopheryl polyethylene glycol 1000 succinate [TPGS], while Koselugo 25 mg capsules contain 36 mg vitamin E as TPGS). Vitamin E can inhibit platelet aggregation and antagonize vitamin K-dependent clotting factors. Daily vitamin E intake that exceeds the recommended or safe limits may increase the risk of bleeding. Supplemental vitamin E is not recommended if daily vitamin E intake (including the amount of vitamin E in Koselugo and supplement) will exceed the recommended or safe limits.

An increased risk of bleeding may occur in patients who are coadministered vitamin-K antagonists or anti-platelet antagonists with Koselugo. Monitor for bleeding in these patients and increase international normalized ratio (INR) monitoring in patients taking a vitamin-K antagonist. Perform anticoagulant assessments more frequently and adjust the dose of vitamin K antagonists or anti-platelet agents as appropriate.

Embryo-Fetal Toxicity. Based on findings from animal studies, Koselugo can cause fetal harm when administered to a pregnant woman. In animal studies, administration of selumetinib to mice during organogenesis caused reduced fetal weight, adverse structural defects, and effects on embryo-fetal survival at approximate exposures >5 times the human exposure at the clinical dose of 25 mg/m2 twice daily. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Koselugo and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Koselugo and for 1 week after the last dose.

Breastfeeding. Due to the potential for adverse reactions in a breastfed child, advise women not to breastfeed during treatment with Koselugo and for 1 week after the last dose.

Concomitant use of Koselugo with a strong or moderate CYP3A4 inhibitor or fluconazole increased selumetinib plasma concentrations, which may increase the risk of adverse reactions. Avoid coadministration of strong or moderate CYP3A4 inhibitors or fluconazole with Koselugo. If coadministration with strong or moderate CYP3A4 inhibitors or fluconazole cannot be avoided, reduce Koselugo dosage.

Concomitant use of Koselugo with a strong or moderate CYP3A4 inducer decreased selumetinib plasma concentrations, which may reduce Koselugo efficacy. Avoid concomitant use of strong or moderate CYP3A4 inducers with Koselugo.

The most common adverse reactions ≥40% are: vomiting, rash (all), abdominal pain, diarrhea, nausea, dry skin, musculoskeletal pain, fatigue, pyrexia, acneiform rash, stomatitis, headache, paronychia, and pruritus.

INDICATION

Koselugo is indicated for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN).


Please see complete Prescribing Information including Patient Information.

You may report side effects related to AstraZeneca products by clicking here.

References: 1. Koselugo [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2020. 2. Data on File, REF-75729, AstraZeneca Pharmaceuticals LP.

References: 1. Korf BR, Rubenstein AE. Neurofibromatosis: A Handbook for Patients, Families, and Health Care Professionals. New York, NY: Thieme Medical Publishers; 2005. 2. Gross AM, Singh G, Akshintala S, et al. Association of plexiform neurofibroma volume changes and development of clinical morbidities in neurofibromatosis 1. Neuro Oncol. 2018;20(12):1643-1651. 3. Anderson JL, Gutmann DH. Neurofibromatosis type 1. In: Islam MP, Roach SE, eds. Neurocutaneous Syndromes. Waltham, MA: Elsevier B.V.; 2015:75-86. Handbook of Clinical Neurology. 3rd series; vol 132. 4. Data on File, REF-75729, AstraZeneca Pharmaceuticals LP. 5. Ferner RE, Huson SM, Thomas N, et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet. 2007;44:81-88. 6. Wolters PL, Burns KM, Martin S, et al. Pain interference in youth with neurofibromatosis type 1 and plexiform neurofibromas and relation to disease severity, social-emotional functioning, and quality of life. Am J Med Genet A. 2015;167A(9):2103-2113. 7. Friedrich RE, Schmelzle R, Hartmann M, Fünsterer C, Mautner V-F. Resection of small plexiform neurofibromas in neurofibromatosis type 1 children. World J Surg Oncol. 2005;3(1):6.

References: 1. Data on File, REF-75729, AstraZeneca Pharmaceuticals LP. 2. Koselugo [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2020. 3. Dombi E, Ardern-Holmes SL, Babovic-Vuksanovic D, et al. Recommendations for imaging tumor response in neurofibromatosis clinical trials. Neurology. 2013;81(suppl 1):S33-S40. 4. Blakeley JO, Plotkin SR. Therapeutic advances for the tumors associated with neurofibromatosis type 1, type 2, and schwannomatosis. Neuro Oncol. 2016;18(5):624-638. 5. Yap YS, McPherson JR, Ong CK, et al. The NF1 gene revisited—from bench to bedside. Oncotarget. 2014;5(15):5873-5892.

References: 1. Koselugo [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2020. 2. Data on File, REF-75729, AstraZeneca Pharmaceuticals LP.

References: 1. Koselugo [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2020. 2. Data on File, REF-75729, AstraZeneca Pharmaceuticals LP.

References: 1. Koselugo [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2020. 2. Data on File, REF-75730, AstraZeneca Pharmaceuticals LP. 3. Data on File, REF-70330, AstraZeneca Pharmaceuticals LP. 4. Data on File, REF-75729, AstraZeneca Pharmaceuticals LP.