Principal Investigator: Nicholas Whipple
Keywords: Oncology , Glioma Department: Pediatric Administration
IRB Number: 00138633
Specialty: Oncology
Sub Specialties:
Recruitment Status: Recruiting

Contact Information

Elias Rios
elias.rios@hsc.utah.edu
801-213-4128

Brief Summary

Primary Objective:

To evaluate the overall response rate (ORR) as determined by an independent radiology review committee (IRC) and measured by the proportion of patients with best overall confirmed response of complete response (CR) or partial response (PR) by Response Assessment in Neuro-Oncology (RANO) criteria following treatment with DAY101 in pediatric patients aged 6 months to 25 years of age with a relapsed or progressive low-grade glioma (LGG) harboring a known activating BRAF alteration.


Secondary Objectives:

• To assess safety and tolerability of DAY101
• To determine the relationship between pharmacokinetics (PK) and drug effects, including efficacy and safety
• To evaluate the effect of DAY101 on the QT interval corrected for heart rate by Fridericia formula (QTcF) prolongation and to explore the effects of DAY101 on electrocardiogram (ECG) parameters
• To determine the ORR based on the treating investigator’s response assessment using RANO criteria
• To determine the ORR based on Response Assessment in Pediatric Neuro-Oncology (RAPNO)–low-grade glioma (LGG) criteria as determined by 1) an IRC and 2) the treating investigator
• To evaluate the duration of progression-free survival (PFS) based on RANO and RAPNO criteria following initiation of DAY101 as determined by 1) an IRC and 2) the treating investigator
• To evaluate the duration of response (DOR) in patients with best overall response of CR or PR based on RANO and RAPNO criteria as determined by 1) an IRC and 2) the treating investigator
• To evaluate time to response (CR or PR based on RANO and RAPNO criteria) following initiation of DAY101 as determined by 1) an IRC and 2) the treating investigator
• To evaluate the clinical benefit rate based on the proportion of patients with best overall response of CR, PR, or stable disease, based on RANO and RAPNO criteria, lasting 12 months or more following initiation of DAY101 as determined by 1) an IRC and 2) the treating investigator
• To evaluate visual acuity (VA) outcomes compared with baseline
• To evaluate the concordance of prior local laboratory BRAF molecular profiling with a central BRAF alteration assay being evaluated by the Sponsor

Exploratory Objectives:

• To compare the response and time to progression following initiation of DAY101 to that of the prior line of systemic therapy
• To characterize changes in total tumor volume following treatment with DAY101 by magnetic resonance imaging (MRI) volumetric image analysis
• To characterize changes in apparent diffusion coefficients following treatment with DAY101 using diffusion-weighted imaging analysis
• To evaluate changes from baseline in quality of life and health utilities measures using the Pediatrics Quality of Life™—Core (PedsQL-Core) module and Patient-Reported Outcomes Measurement Information System (PROMIS®) assessment
• To describe improvement in motor function compared with baseline
• To determine the durability of response following discontinuation of DAY101 for patients with a radiographic response to DAY101 (CR or PR as based on RANO and RAPNO criteria) as determined by 1) an IRC and 2) the treating Investigator
• To evaluate time to initiation of next treatment following discontinuation of DAY101

 

 

 

Study Objectives and Endpoints PRIMARY OBJECTIVE AND ENDPOINTS

OBJECTIVE

ENDPOINTS

 

  • To evaluate the efficacy of DAY101 as measured by the overall response rate (ORR) as determined by an independent radiology review committee (IRC) following treatment with DAY101 in pediatric patients aged 6 months to 25 years of age with a relapsed or progressive LGG harboring a known activating BRAF alteration
  • ORR, defied as the proportion of patients with best overall confirmed response of complete response (CR) or partial response (PR) as determined by the Response Assessment in Neuro-Oncology (RANO) criteria

SECONDARY OBJECTIVES AND ENDPOINTS

OBJECTIVE

ENDPOINTS

 

• To assess the safety and tolerability of DAY101

 

 

• Type, frequency, and severity of AEs and laboratory abnormalities

 

 

• To determine the relationship between pharmacokinetics (PK) and drug effects, including efficacy and safety

 

 

• Pharmacokinetic profile of DAY101 (e.g., area under the concentration-time curve [AUC], Cmin, etc.)

 

 

• To evaluate the effect of DAY101 on the QT interval corrected for heart rate by Fridericia’s formula (QTcF) prolongation and to explore the effects of DAY101 on electrocardiogram (ECG) parameters

 

 

• Change from baseline QT interval corrected for HR by Fridericia’s formula (ΔQTcF)

• Change from baseline PR interval (ΔPR)

• Change from baseline QRS interval (ΔQRS)

• Change from baseline heart rate (ΔHR)

• ECG waveform morphology

 

 

• To determine the ORR based on the treating investigator’s response assessment using RANO criteria

 

 

• Measured by the proportion of patients with best overall confirmed response of CR or PR by RANO criteria

 

 

• To determine the ORR based on Response Assessment in Pediatric Neuro-Oncology (RAPNO)–low-grade glioma (LGG) criteria as determined by 1) an IRC and 2) the treating investigator

 

 

• Measured by the proportion of patients with best overall confirmed response of CR or PR by RAPNO-LGG criteria

 

 

• To evaluate the duration of progression-free survival (PFS) based on RANO and RAPNO criteria following initiation of DAY101 as determined by 1) an IRC and 2) the treating investigator

 

 

• Measured by the time following initiation of DAY101 to progression or death in patients treated with DAY101

 

 

• To evaluate the duration of response (DOR) in patients with best overall response of CR or PR based on RANO and RAPNO criteria as determined by 1) an IRC and 2) the treating investigator

 

 

• Measured by the length of response in patients with best overall confirmed response of CR or PR by RANO criteria

 

Inclusion Criteria

SELECTION OF STUDY POPULATION
Potential patients and/or their parents must sign an informed consent form (ICF) and pediatric assent form, where applicable, before any study-specific screening tests may be conducted.

Inclusion Criteria

1.     Age 6 months to 25 years with a relapsed or progressive LGG with a documented known activating BRAF alteration, as identified through molecular assays as routinely performed at CLIA or other similarly certified laboratories

2.    Confirmation of histopathologic diagnosis of LGG from either original diagnosis or relapse/progression

3.    Patients must have received at least 1 line of systemic therapy and have documented evidence of radiographic progression

4.    Patient must have at least 1 measurable lesion as defined by RANO criteria (T1-weighted enhancing lesion that can be reproducibly measured in at least 2 dimensions of at least 10 mm, visible on 2 or more axial slices that are                 preferably, at most, 5 mm apart with 0- mm skip). Imaging must be performed within 28 days of the initiation of treatment

5.    Radiation therapy to the measurable lesion(s) must be completed at least 6 months prior to administration of DAY101. Patients who have documented radiographic progression less than 6 months from radiotherapy in 1 or more                 measurable lesions are eligible

6.    Karnofsky (those 16 years and older) or Lansky (those younger than 16 years) performance score of at least 50. Patients who are unable to walk because of paralysis, but who are able to sit in a wheelchair, will be considered                     ambulatory for the purpose of  assessing the performance score

7.    Patients must have fully recovered from the acute toxic effects of all prior anticancer chemotherapy and have undergone the following washout periods, as applicable:
       a) Myelosuppressive chemotherapy: At least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea)
       b) Radiation therapy (XRT): At least 14 days after the last dose fraction of XRT
       c) Stem cell transplant or adoptive cell therapy: At least 100 days must have elapsed after cell infusion
       d) Investigational agent or any other anticancer therapy not defined above: At least 4 weeks prior to planned start of DAY101 or 5 half-lives, whichever is shorter

8.   Chronic toxicities from prior anticancer therapy must be stable and at Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grade ≤ 2

9.   Patients must have fully recovered from any prior surgery

10. Confirmation that an archival tumor tissue sample is available. If an archival tumor tissue sample is not available, a fresh biopsy should be performed at baseline.

11. Patients must have adequate hematologic function, as defined by the following:
      a) Absolute neutrophil count ≥ 1000/mm3
      b) Platelet count ≥ 75.0 × 109/L (transfusions allowed per institutional guidelines; last transfusion > 2 weeks prior to C1D1)
      c) Hemoglobin ≥ 10.0 g/dL (transfusions allowed per institutional guidelines; last transfusion > 4 weeks prior to C1D1)
      d) Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor (e.g., Neulasta®) or 7 days for short-acting growth factor

12. Patients must have adequate hepatic and renal function, defined as the following:
      a) Total bilirubin ≤ 1.5 × upper limit of normal (ULN) for age (patients with documented Gilbert’s Disease may be enrolled with Sponsor approval and total bilirubin ≤ 2.0 × ULN)
      b) Serum glutamic-pyruvic transaminase (SGPT)/alanine aminotransferase (ALT) ≤ 2.5 × ULN
      c) Serum glutamic-oxaloacetic transaminase (SGOT)/ Aspartate transaminase (AST) ≤ 2.5 × ULN
      d) International Normalized Ratio (INR) < 2.0
      e) Serum creatinine within normal limits (as presented in Section 4.1), or estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2 based on local institutional practice for determination

 

Age

Maximum Serum Creatinine (mg/dL)

Maximum Serum Creatinine (mmol/L)

Male

Female

Male

Female

6 months to < 1 year

0.5

0.5

44

44

1 to < 2 years

0.6

0.6

53

53

2 to < 6 years

0.8

0.8

71

71

6 to < 10 years

1

1

88

88

10 to < 13 years

1.2

1.2

106

106

13 to < 16 years

1.5

1.4

132

124

≥ 16 years

1.7

1.4

150

124

13. Thyroid function tests must be consistent with stable thyroid function. Patients on a stable dose of thyroid replacement therapy for a minimum of 3 weeks before starting DAY101 are eligible

14. Left ventricular ejection fraction (LVEF) of ≥ 50% or greater as measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan, or fractional shortening (FS) ≥ 25% as measured by echocardiogram (ECHO), within          28 days before the first dose of DAY101. If normal practice at the institution is to provide the LVEF result as a range of values, then the upper value of the range will be used to determine the result

15. Patients receiving steroids for tumor-associated symptoms must be on a stable dose (e.g., no initial/loading dose, no increase or decrease) for 14 days prior to C1D1

16. Ability to comply with treatment, laboratory monitoring, and required clinic visits for the duration of study participation

17. Willingness of male and female patients with reproductive potential to use double effective birth control methods, defined as one used by the patient and another by his/her partner, for the duration of treatment and for 180 days                  following the last dose of study drug. Effective birth control methods are described in Appendix I

18. Ability to swallow tablets

19. Parent/guardian of child or adolescent patient has the ability to understand, agree to, and sign the study informed consent form (ICF) and applicable pediatric assent form before initiation of any protocol-related procedures; patient              has the ability to give assent, as applicable, at the time of parental/guardian consent

 

Exclusion Criteria

Exclusion Criteria

Patients meeting any of the following criteria are to be excluded from study participation:

1.  Patient’s tumor has additional previously-known activating molecular alterations (e.g., histone mutation, IDH1/2 mutations, FGFR mutations or fusions, MYBL alterations, NF1 somatic or germline mutations)

2.  Patient has symptoms of clinical progression without radiographically recurrent or radiographically progressive disease

3.  Known or suspected diagnosis of neurofibromatosis type 1 (NF-1) via genetic testing or current diagnostic criteria

4.  History of any major disease, other than the diagnosis of LGG, that might interfere with safe protocol participation

5.  Patients with a history or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO), or ophthalmopathy present at baseline who would be considered a risk factor for CSR or RVO. Ophthalmological findings               secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor, or strabismus) will NOT be considered a significant abnormality for the purposes of this study

6.  Major surgery within 14 days (2 weeks) prior to C1D1 (does not include central venous access, cyst fenestration or cyst drainage, or ventriculo-peritoneal shunt placement or revision)

7.  Clinically significant active cardiovascular disease, or history of myocardial infarction, or deep vein thrombosis/pulmonary embolism within 6 months prior to C1D1, ongoing cardiomyopathy, or current prolonged QT interval corrected for         heart rate by Fridericia’s formula (QTcF) interval > 440 ms based on triplicate ECG average

8.  Current enrollment in any other investigational treatment study. Participation on a concurrent observational or bio-sampling study is allowed

9.  Active systemic bacterial, viral, or fungal infection

10. Nausea and vomiting ≥ National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 5.0 Grade 2, malabsorption requiring supplementation, or significant bowel or stomach resection that would preclude            adequate absorption of DAY101

11. Patients who are neurologically unstable despite adequate treatment (e.g., uncontrolled seizures)

12. Current treatment with a strong cytochrome P450 2C8 (CYP2C8) inhibitor or inducer other than those allowed per Section 5.3.2. Medications that are substrates of CYP2C8 are allowed but should be used with caution

13. Pregnancy or lactation

14. History of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, Stevens Johnsons syndrome (SJS), or hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to            any other excipient present in the pharmaceutical form of the investigational medicinal product

15. Other unspecified reasons that, in the opinion of the investigator, make the patient unsuitable for enrollment