Next Generation Personalized Neuroblastoma Therapy with Ribociclib and Ceritinib, Trametinib, or HDM2 Inhibitor HDM201 in Treating Younger Patients with High-Risk Neuroblastoma

Status: Active

Description

This phase I trial studies the side effects and best dose of ribociclib when given together with ceritinib, and HDM2 inhibitor HDM201, and to also see how well ribociclib and ceritinib, trametinib, or HDM2 inhibitor HDM201 work in treating patients with high-risk neuroblastoma. Ribociclib, ceritinib, trametinib, and HDM2 inhibitor HDM201 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Assigning patients to different treatment groups with ribociclib and ceritinib, trametinib, or HDM2 inhibitor HDM201 based on genetic testing may work better in treating neuroblastoma.

Eligibility Criteria

Inclusion Criteria

  • PART 1 INCLUSION CRITERIA
  • Subjects must have had histologic verification of neuroblastoma at original diagnosis or relapse
  • Subjects must have received frontline standard therapy for high-risk neuroblastoma and meet one of the following three conditions for recurrent/progressive, refractory, or persistent disease * Recurrent/progressive disease at any time prior to enrollment (regardless of overall response to frontline therapy) * Refractory disease: persistent sites of disease after achieving a best overall response of stable disease to frontline therapy after a minimum of 4 cycles of induction therapy AND patient has never had recurrent/progressive disease * Persistent disease: persistent sites of disease after achieving a best overall response of partial response to frontline therapy after a minimum of 4 cycles of induction therapy AND patient has never had recurrent/progressive disease
  • Subjects must have either measurable and/or evaluable disease
  • Must have neuroblastoma lesion(s) amenable to non-significant risk biopsy for next generation sequencing (NGS) profiling at Foundation Medicine; biopsies of the brain; lung/mediastinum; pancreas; endoscopic procedures extending beyond the lung, stomach, or bowel; or other significant risk biopsies will not be performed as part of this study; if a subject has tumor tissue archived from a previous biopsy, that tissue may be sent to Foundation Medicine for NGS and an additional biopsy will not be required
  • Subject’s current disease state must be one for which there is no known curative therapy
  • Subject/parental/guardian permission (informed consent), and child assent for subjects >= 7 years
  • PART 2 GROUP 1 INCLUSION CRITERIA: Subject has high-risk neuroblastoma with a protocol-defined genomic aberration that allows assignment to Group 1
  • PART 2 GROUP 1 INCLUSION CRITERIA: Performance status: * Karnofsky score >= 50 for subjects >16 years of age * Lansky score >= 50 for subjects =< 16 years of age * Note: subjects who are unable to walk because of paralysis, but who are mobile in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
  • PART 2 GROUP 1 INCLUSION CRITERIA: A sufficient interval must have elapsed between the last dose of prior anti-cancer therapy (including cytotoxic and biological therapies) and enrollment in this study, to allow recovery from the acute toxic effects of all prior anti-cancer therapy: * Myelosuppressive chemotherapy: At least 21 days after the last dose of myelosuppressive chemotherapy * Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor * Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent * Immunotherapy: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1; at least 42 days after therapy with a cellular immunotherapy or anti-cancer vaccine * Radiation therapy: At least 14 days after local palliative radiation therapy (XRT) (small port); >= 6 weeks must have elapsed since treatment with therapeutic doses of metaiodobenzylguanidine (MIBG); >= 6 months must have elapsed from total body irradiation (TBI), craniospinal XRT or 50% radiation of pelvis * Stem Cell Transplant (SCT): At least 12 weeks after myeloablative therapy with autologous stem cell transplant (timed from start of protocol therapy); subjects must meet adequate bone marrow function definition (see organ function requirements, below) post-myeloablative therapy; patients who received stem cell reinfusion following non-myeloablative therapy are eligible once they meet peripheral blood count criteria below * Subjects with prior treatment with compound/s with the same mode of action used in one of the treatment groups are eligible if they have not previously received prior treatment with BOTH agents in the combination
  • PART 2 GROUP 1 INCLUSION CRITERIA: Peripheral absolute neutrophil count (ANC) >= 1000/mm^3 (1.0 x 10^9/L) without granulocyte growth factor for >= 7 days
  • PART 2 GROUP 1 INCLUSION CRITERIA: Platelet count >= 75,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
  • PART 2 GROUP 1 INCLUSION CRITERIA: Hemoglobin (Hgb) >= 8 g/dL (may receive red blood cell [RBC] transfusion)
  • PART 2 GROUP 1 INCLUSION CRITERIA: These criteria must be met by all subjects, regardless of bone marrow involvement with tumor
  • PART 2 GROUP 1 INCLUSION CRITERIA: Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 OR a serum creatinine based on age/gender normal as follows: * 1 to < 2 years: Male and female: 0.6 * 2 to < 6 years: Male and female: 0.8 * 6 to < 10 years: Male and female: 1 * 10 to < 13 years: Male and female: 1.2 * 13 to < 16 years: Male: 1.5; Female: 1.4 * 16 years and above: Male: 1.7; Female: 1.4
  • PART 2 GROUP 1 INCLUSION CRITERIA: Total serum bilirubin (sum of conjugated + unconjugated) =< 1.5x upper limit of normal (ULN), except for subjects with Gilbert’s Syndrome who may be included if total bilirubin is =< 3.0 x ULN and direct bilirubin is =< 1.5 x ULN
  • PART 2 GROUP 1 INCLUSION CRITERIA: Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L
  • PART 2 GROUP 1 INCLUSION CRITERIA: Corrected QTc =< 480 msec
  • PART 2 GROUP 1 INCLUSION CRITERIA: Shortening Fraction > 27%
  • PART 2 GROUP 1 INCLUSION CRITERIA: All subjects or a parent/guardian must sign written informed consent
  • PART 2 GROUP 1 INCLUSION CRITERIA: Subjects taking capsule formulations must be able to swallow capsules
  • PART 2 GROUP 1 INCLUSION CRITERIA: Males and females who are sexually active must agree to use effective contraception during and for three months after treatment
  • PART 2 GROUP 2A INCLUSION CRITERIA: Subject has high-risk neuroblastoma with a protocol-defined genomic aberration that allows assignment to Group 2
  • PART 2 GROUP 2A INCLUSION CRITERIA: Performance status: * Karnofsky score >= 50 for subjects >16 years of age * Lansky score >= 50 for subjects =< 16 years of age * Note: subjects who are unable to walk because of paralysis, but who are mobile in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
  • PART 2 GROUP 2A INCLUSION CRITERIA: A sufficient interval must have elapsed between the last dose of prior anti-cancer therapy (including cytotoxic and biological therapies) and enrollment in this study, to allow recovery from the acute toxic effects of all prior anti-cancer therapy: * Myelosuppressive chemotherapy: At least 21 days after the last dose of myelosuppressive chemotherapy * Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor * Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent * Immunotherapy: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1; at least 42 days after therapy with a cellular immunotherapy or anti-cancer vaccine * Radiation therapy: At least 14 days after local palliative XRT (small port); >= 6 weeks must have elapsed since treatment with therapeutic doses of MIBG; >= 6 months must have elapsed from TBI, craniospinal XRT or 50% radiation of pelvis * SCT: At least 12 weeks after myeloablative therapy with autologous stem cell transplant (timed from start of protocol therapy); subjects must meet adequate bone marrow function definition (see organ function requirements, below) post-myeloablative therapy; patients who received stem cell reinfusion following non-myeloablative therapy are eligible once they meet peripheral blood count criteria below * Subjects with prior treatment with compound/s with the same mode of action used in one of the treatment groups are eligible if they have not previously received prior treatment with BOTH agents in the combination
  • PART 2 GROUP 2A INCLUSION CRITERIA: Peripheral ANC >= 1000/mm^3 (1.0 x 10^9/L) without granulocyte growth factor for >= 7 days
  • PART 2 GROUP 2A INCLUSION CRITERIA: Hgb >= 8 g/dL (may receive RBC transfusion)
  • PART 2 GROUP 2A INCLUSION CRITERIA: These criteria must be met by all subjects, regardless of bone marrow involvement with tumor
  • PART 2 GROUP 2A INCLUSION CRITERIA: Creatinine clearance or radioisotope GFR >= 70 mL/min/1.73 m^2 OR a serum creatinine based on age/gender normal as follows: * 1 to < 2 years: Male and female: 0.6 * 2 to < 6 years: Male and female: 0.8 * 6 to < 10 years: Male and female: 1 * 10 to < 13 years: Male and female: 1.2 * 13 to < 16 years: Male: 1.5; Female: 1.4 * 16 years and above: Male: 1.7; Female: 1.4
  • PART 2 GROUP 2A INCLUSION CRITERIA: Total serum bilirubin (sum of conjugated + unconjugated) =< 1.5x ULN, except for subjects with Gilbert’s Syndrome who may be included if total bilirubin is =< 3.0 x ULN and direct bilirubin is =< 1.5 x ULN
  • PART 2 GROUP 2A INCLUSION CRITERIA: SGPT (ALT) =< 110 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L
  • PART 2 GROUP 2A INCLUSION CRITERIA: Corrected QTc =< 480 msec
  • PART 2 GROUP 2A INCLUSION CRITERIA: Shortening Fraction > 27%
  • PART 2 GROUP 2A INCLUSION CRITERIA: All subjects or a parent/guardian must sign written informed consent
  • PART 2 GROUP 2A INCLUSION CRITERIA: Subjects taking capsule formulations must be able to swallow capsules
  • PART 2 GROUP 2A INCLUSION CRITERIA: Males and females who are sexually active must agree to use effective contraception during and for three months after treatment
  • PART 2 GROUP 3 INCLUSION CRITERIA: Subject has high-risk neuroblastoma with a protocol-defined genomic aberration that allows assignment to Group 3
  • PART 2 GROUP 3 INCLUSION CRITERIA: Performance status: * Karnofsky score >= 50 for subjects >16 years of age * Lansky score >= 50 for subjects =< 16 years of age * Note: subjects who are unable to walk because of paralysis, but who are mobile in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
  • PART 2 GROUP 3 INCLUSION CRITERIA: A sufficient interval must have elapsed between the last dose of prior anti-cancer therapy (including cytotoxic and biological therapies) and enrollment in this study, to allow recovery from the acute toxic effects of all prior anti-cancer therapy: * Myelosuppressive chemotherapy: At least 21 days after the last dose of myelosuppressive chemotherapy * Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor * Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent * Immunotherapy: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1; at least 42 days after therapy with a cellular immunotherapy or anti-cancer vaccine * Radiation therapy: At least 14 days after local palliative XRT (small port); >= 6 weeks must have elapsed since treatment with therapeutic doses of metaiodobenzylguanidine (MIBG); >= 6 months must have elapsed from TBI, craniospinal XRT or 50% radiation of pelvis * SCT: At least 12 weeks after myeloablative therapy with autologous stem cell transplant (timed from start of protocol therapy); subjects must meet adequate bone marrow function definition (see organ function requirements, below) post-myeloablative therapy; patients who received stem cell reinfusion following non-myeloablative therapy are eligible once they meet peripheral blood count criteria below * Subjects with prior treatment with compound/s with the same mode of action used in one of the treatment groups are eligible if they have not previously received prior treatment with BOTH agents in the combination
  • PART 2 GROUP 3 INCLUSION CRITERIA: Peripheral ANC >= 1000/mm^3 (1.0 x 10^9/L) without granulocyte growth factor for >= 7 days
  • PART 2 GROUP 3 INCLUSION CRITERIA: Platelet count >= 75,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
  • PART 2 GROUP 3 INCLUSION CRITERIA: Hgb >= 8 g/dL (may receive RBC transfusion)
  • PART 2 GROUP 3 INCLUSION CRITERIA: These criteria must be met by all subjects, regardless of bone marrow involvement with tumor
  • PART 2 GROUP 3 INCLUSION CRITERIA: Creatinine clearance or radioisotope GFR >= 70 mL/min/1.73 m^2 OR a serum creatinine based on age/gender normal as follows: * 1 to < 2 years: Male and female: 0.6 * 2 to < 6 years: Male and female: 0.8 * 6 to < 10 years: Male and female: 1 * 10 to < 13 years: Male and female: 1.2 * 13 to < 16 years: Male: 1.5; Female: 1.4 * 16 years and above: Male: 1.7; Female: 1.4
  • PART 2 GROUP 3 INCLUSION CRITERIA: Total serum bilirubin (sum of conjugated + unconjugated) =< 1.5x ULN, except for subjects with Gilbert’s Syndrome who may be included if total bilirubin is =< 3.0 x ULN and direct bilirubin is =< 1.5 x ULN
  • PART 2 GROUP 3 INCLUSION CRITERIA: Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L
  • PART 2 GROUP 3 INCLUSION CRITERIA: Corrected QTc =< 480 msec
  • PART 2 GROUP 3 INCLUSION CRITERIA: Shortening Fraction > 27%
  • PART 2 GROUP 3 INCLUSION CRITERIA: All subjects or a parent/guardian must sign written informed consent
  • PART 2 GROUP 3 INCLUSION CRITERIA: Subjects taking capsule formulations must be able to swallow capsules
  • PART 2 GROUP 3 INCLUSION CRITERIA: Males and females who are sexually active must agree to use effective contraception during and for three months after treatment

Exclusion Criteria

  • PART 1 EXCLUSION CRITERIA: Subjects with concurrent severe and/or uncontrolled concurrent medical conditions that could compromise participation in the study (e.g., chronic medical or psychiatric condition or laboratory abnormality, uncontrolled hypertension and/or diabetes mellitus, clinically significant pulmonary disease, clinically significant neurological disorder, active or uncontrolled infection (including hepatitis A, B or C, human immunodeficiency virus [HIV] [testing is not mandatory])
  • PART 1 EXCLUSION CRITERIA: Subjects < 0.5 M^2
  • PART 1 EXCLUSION CRITERIA: Pregnant or lactating females
  • PART 1 EXCLUSION CRITERIA: Potential subjects and/or parents/guardians who, in the opinion of the investigative team, are likely to be non-compliant with study schedules or procedures
  • PART 2 GROUP 1 EXCLUSION CRITERIA: Subjects who are currently receiving treatment with agents that are known to cause QTc prolongation in humans; agents causing a strong signal will be prohibited
  • PART 2 GROUP 1 EXCLUSION CRITERIA: Subjects who are currently receiving treatment with drugs or herbal medications that can impact drug metabolism
  • PART 2 GROUP 1 EXCLUSION CRITERIA: Subjects with concurrent severe and/or uncontrolled concurrent medical conditions that could compromise participation in the study (e.g., chronic medical or psychiatric condition or laboratory abnormality, uncontrolled hypertension and/or diabetes mellitus, clinically significant pulmonary disease, clinically significant neurological disorder, active or uncontrolled infection (including hepatitis A, B or C, human immunodeficiency virus [HIV] [testing is not mandatory])
  • PART 2 GROUP 1 EXCLUSION CRITERIA: Other concomitant therapies * Corticosteroids that were initiated for anti-tumor effect within seven days prior to initiation of protocol therapy * Investigational drugs * Anti-cancer agents * Hematologic growth factors * Radiation therapy
  • PART 2 GROUP 1 EXCLUSION CRITERIA: Pregnant or lactating females
  • PART 2 GROUP 1 EXCLUSION CRITERIA: Potential subjects and/or parents/guardians who, in the opinion of the investigative team, are likely to be non-compliant with study schedules or procedures
  • PART 2 GROUP 1 EXCLUSION CRITERIA: Sexually active males unless they use a condom during intercourse while on protocol therapy and for 3 months after study drug discontinuation and thus do not attempt to father a child in this period
  • PART 2 GROUP 2A EXCLUSION CRITERIA: Subjects who are currently receiving treatment with agents that are known to cause QTc prolongation in humans; agents causing a strong signal will be prohibited
  • PART 2 GROUP 2A EXCLUSION CRITERIA: Subjects who are currently receiving treatment with drugs or herbal medications that can impact drug metabolism
  • PART 2 GROUP 2A EXCLUSION CRITERIA: Subjects with concurrent severe and/or uncontrolled concurrent medical conditions that could compromise participation in the study (e.g., chronic medical or psychiatric condition or laboratory abnormality, uncontrolled hypertension and/or diabetes mellitus, clinically significant pulmonary disease, clinically significant neurological disorder, active or uncontrolled infection (including hepatitis A, B or C, human immunodeficiency virus [HIV] [testing is not mandatory])
  • PART 2 GROUP 2A EXCLUSION CRITERIA: Other concomitant therapies * Corticosteroids that were initiated for anti-tumor effect within seven days prior to initiation of protocol therapy * Investigational drugs * Anti-cancer agents * Hematologic growth factors * Radiation therapy
  • PART 2 GROUP 2A EXCLUSION CRITERIA: Pregnant or lactating females
  • PART 2 GROUP 2A EXCLUSION CRITERIA: Potential subjects and/or parents/guardians who, in the opinion of the investigative team, are likely to be non-compliant with study schedules or procedures
  • PART 2 GROUP 2A EXCLUSION CRITERIA: Sexually active males unless they use a condom during intercourse while on protocol therapy and for 3 months after study drug discontinuation and thus do not attempt to father a child in this period
  • PART 2 GROUP 3 EXCLUSION CRITERIA: Subjects who are currently receiving treatment with agents that are known to cause QTc prolongation in humans; agents causing a strong signal will be prohibited
  • PART 2 GROUP 3 EXCLUSION CRITERIA: Subjects who are currently receiving treatment with drugs or herbal medications that can impact drug metabolism
  • PART 2 GROUP 3 EXCLUSION CRITERIA: Subjects with concurrent severe and/or uncontrolled concurrent medical conditions that could compromise participation in the study (e.g., chronic medical or psychiatric condition or laboratory abnormality, uncontrolled hypertension and/or diabetes mellitus, clinically significant pulmonary disease, clinically significant neurological disorder, active or uncontrolled infection (including hepatitis A, B or C, human immunodeficiency virus [HIV] [testing is not mandatory])
  • PART 2 GROUP 3 EXCLUSION CRITERIA: Other concomitant therapies * Corticosteroids that were initiated for anti-tumor effect within seven days prior to initiation of protocol therapy * Investigational drugs * Anti-cancer agents * Hematologic growth factors * Radiation therapy
  • PART 2 GROUP 3 EXCLUSION CRITERIA: Pregnant or lactating females
  • PART 2 GROUP 3 EXCLUSION CRITERIA: Potential subjects and/or parents/guardians who, in the opinion of the investigative team, are likely to be non-compliant with study schedules or procedures
  • PART 2 GROUP 3 EXCLUSION CRITERIA: Sexually active males unless they use a condom during intercourse while on protocol therapy and for 3 months after study drug discontinuation and thus do not attempt to father a child in this period

Locations & Contacts

Pennsylvania

Philadelphia
Children's Hospital of Philadelphia
Status: Active
Contact: Yael P. Mosse
Phone: 215-590-0965
Email: mosse@chop.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To define the genomic landscape of relapsed and refractory high-risk neuroblastoma. (Part 1)

II. Determine the frequency by which a comprehensive next generation sequencing (NGS)-based assay designed to detect all known pediatric cancer somatic mutations leads to neuroblastoma subject benefit in terms of objective anti-tumor activity. (Part 1)

III. To characterize the safety and tolerability of combining ceritinib and ribociclib in subjects with ALK-driven relapsed/refractory neuroblastoma. (Part 2, Group 1)

IV. To identify the recommended phase 2 dose (RP2D) for combination therapy with ceritinib and ribociclib in subjects with relapsed/refractory ALK-driven neuroblastoma. (Part 2, Group 1)

V. To describe the pharmacokinetic (PK) profile of the combinatorial targeted therapy. (Part 2, Group 1)

VI. To describe whether the assigned targeted therapy can mediate anti-tumor effects in subjects with relapsed and primary refractory high-risk neuroblastoma within the context of phase 1/phase1b biomarker-driven trials. (Part 2, Group 1)

VII. To characterize the safety and tolerability profile of trametinib as a single agent in subjects with RAS-driven relapsed/refractory neuroblastoma. (Part 2, Group 2A)

VIII. To describe the PK profile of the single-agent targeted therapy. (Part 2, Group 2A)

IX. To describe whether the assigned targeted therapy can mediate anti-tumor effects in subjects with relapsed and primary refractory high-risk neuroblastoma within the context of phase 1/phase1b biomarker-driven trials. (Part 2, Group 2A)

X. To characterize the safety and tolerability of HDM2 inhibitor HDM201 (HDM201) in subjects with relapsed/refractory TP53 wild-type neuroblastoma. (Part 2, Group 3)

XI. To identify the RP2D dose for HDM201 in subjects with relapsed/refractory TP53 wild-type neuroblastoma.

XII. To describe the PK profile of the single-agent targeted therapy. (Part 2, Group 3)

XIII. To describe whether the assigned targeted therapy can mediate anti-tumor effects in subjects with relapsed and primary refractory high-risk neuroblastoma within the context of phase 1/phase1b biomarker-driven trials. (Part 2, Group 3)

SECONDARY OBJECTIVES:

I. Define the clonal evolution of relapsed neuroblastoma genomes by comparing matched tumor samples (diagnosis and recurrence) for detection of mutations, copy number alterations and translocations. (Part 1)

II. Establish subject-derived xenografts to allow for direct comparison of anti-tumor activity in the preclinical and clinical settings, and to establish systems to study salvage therapies at the time of tumor progression. (Part 1)

III. Prospectively determine the overall frequency of cell free deoxyribonucleic acid (DNA) (cfDNA) detection and the profile of acquired somatic mutations in peripheral blood samples at study entry and at each anti-tumor evaluation time point (separate companion protocol). (Part 1)

OUTLINE:

PART 1: All patients undergo tumor biopsy and genetic molecular analysis.

PART 2: This is a dose-escalation study of ribociclib and HDM2 inhibitor HDM201. Patients with results from Part 1 indicating ALK gene mutation, MAPK gene mutation, CDK gene mutation, or TP53 wild type are assigned to 1 of 3 groups.

GROUP 1: Patients with ALK-driven relapsed/refractory neuroblastoma receive ceritinib orally (PO) daily on days 1-28 and ribociclib PO daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

GROUP 2A: Patients with RAS-driven relapsed/refractory neuroblastoma receive trametinib PO daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

GROUP 3: Patients with relapsed/refractory TP53 wild-type neuroblastoma receive HDM2 inhibitor HDM201 PO on days 1 and 8. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
Children's Hospital of Philadelphia

Principal Investigator
Yael P. Mosse

Trial IDs

Primary ID 16ST011
Secondary IDs NCI-2017-01870, 14-011071, NEPENTHE
Clinicaltrials.gov ID NCT02780128