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A Study of Oral LOXO-292 in Pediatric Patients With Advanced Solid or Primary Central Nervous System Tumors (LIBRETTO-121)

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ClinicalTrials.gov Identifier: NCT03899792
Recruitment Status : Recruiting
First Posted : April 2, 2019
Last Update Posted : October 4, 2019
Sponsor:
Information provided by (Responsible Party):
Loxo Oncology, Inc.

Brief Summary:
This is an open-label, multi-center Phase 1/2 study of oral LOXO-292 in pediatric patients with an activating RET alteration and an advanced solid or primary CNS tumor.

Condition or disease Intervention/treatment Phase
Medullary Thyroid Cancer Infantile Myofibromatosis Infantile Fibrosarcoma Papillary Thyroid Cancer Soft Tissue Sarcoma Drug: LOXO-292 Phase 1 Phase 2

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

Detailed Description:
This study includes 2 parts: phase 1 (dose escalation) and phase 2 (dose expansion). In phase 1, patients will be enrolled using a rolling 6 dose escalation scheme. The starting dose of LOXO-292 is equivalent to the adult recommended phase 2 dose of 160mg BID. Once the MTD and/or RP2D is identified, patients will be enrolled to one of four phase 2 dose expansion cohorts depending on tumor histology and tumor genotype. Cycle length will be 28 days.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Study of the Oral RET Inhibitor LOXO 292 in Pediatric Patients With Advanced RET-Altered Solid or Primary Central Nervous System Tumors
Actual Study Start Date : July 1, 2019
Estimated Primary Completion Date : November 2021
Estimated Study Completion Date : October 2022


Arm Intervention/treatment
Experimental: LOXO-292
Phase 1- Dose Escalation and determination of MTD; multiple dose levels of LOXO-292 to be evaluated; Phase 2 - The maximum tolerated dose (MTD)/recommended dose from Phase 1
Drug: LOXO-292
Oral LOXO-292




Primary Outcome Measures :
  1. To determine the safety of oral LOXO-292 in pediatric patients with advanced solid tumors: Dose limiting toxicities (DLTs) [ Time Frame: During the first 28-day cycle of LOXO-292 treatment ]
    For Phase 1

  2. To determine the safety of oral LOXO-292 in pediatric patients with primary central nervous system (CNS) tumors: Dose limiting toxicities (DLTs) [ Time Frame: During the first 28-day cycle of LOXO-292 treatment ]
    For Phase 1

  3. ORR based on RECIST 1.1 per IRC [ Time Frame: Baseline to Progressive Disease or Death due to any cause (Estimated up to 12 months) ]
    For Phase 2

  4. ORR based on RANO per IRC [ Time Frame: Baseline to Progressive Disease or Death due to any cause (Estimated up to 12 months) ]
    For Phase 2


Secondary Outcome Measures :
  1. Plasma concentrations of LOXO-292 [ Time Frame: Days 1 & 8 of Cycle 1, Day 1 of Cycle 3 and Day 8 after Intra-patient Dose Escalation (each cycle is 28 days) ]
    Phase 1

  2. AUC0-24 of LOXO-292 [ Time Frame: Days 1 & 8 of Cycle 1, Day 1 of Cycle 3 and Day 8 after Intra-patient Dose Escalation (each cycle is 28 days) ]
    Phase 1 & Phase 2

  3. Cmax of LOXO-292 [ Time Frame: Days 1 & 8 of Cycle 1, Day 1 of Cycle 3 and Day 8 after Intra-patient Dose Escalation (each cycle is 28 days) ]
    Phase 1 & Phase 2

  4. Tmax of LOXO-292 [ Time Frame: Days 1 & 8 of Cycle 1, Day 1 of Cycle 3 and Day 8 after Intra-patient Dose Escalation (each cycle is 28 days) ]
    Phase 1 & Phase 2

  5. Recommended LOXO-292 Dose for Phase 2 (Maximum Tolerated Dose [MTD]) [ Time Frame: Cycle 1 (28 days) ]
    For Phase 1

  6. To assess the preliminary anti-tumor activity of LOXO-292 in pediatric patients with tumors harboring an activating RET alteration as determined by ORR based on RECIST v1.1 [ Time Frame: Baseline to Progressive Disease or Death due to any cause (Estimated up to 12 months) ]
    For Phase 1

  7. Changes from baseline in pain measures as measured by Wong Baker Faces scales. Wong-Baker Faces Pain Scale includes pictures of facial expressions with correlating scores of 0 being 'no hurt' and 10 being 'hurts worst'. [ Time Frame: Up to 24 months ]
    For Phase 1

  8. Changes from baseline in health related quality of life measures as measured by Pediatric Quality of Life Inventory Core. PedsQoL includes a list of problems with scores of 0 being 'never a problem' and 4 being 'almost always a problem'. [ Time Frame: Up to 24 months ]
    For Phase 1

  9. Objective Response Rate as assessed by RECIST v1.1, as assessed by investigator [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in patients who have not progressed. ]
    For Phase 2

  10. Objective Response Rate as assessed by RANO, as assessed by investigator [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in patients who have not progressed. ]
    For Phase 2

  11. Duration of response (DOR) as assessed by the Investigator [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in patients who have not progressed. ]
    For Phase 2

  12. Duration of response (DOR) as assessed by the IRC [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in patients who have not progressed. ]
    For Phase 2

  13. Progression free survival (PFS) as assessed by the Investigator [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in patients who have not progressed. ]
    For Phase 2

  14. Progression free survival (PFS) as assessed by the IRC [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in patients who have not progressed. ]
    For Phase 2

  15. Overall survival (OS) [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in patients who have not progressed. ]
    For Phase 2

  16. Clinical Benefit Rate (by Investigator) [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in patients who have not progressed. ]
    For Phase 2

  17. Clinical Benefit Rate (by IRC) [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in patients who have not progressed. ]
    For Phase 2

  18. Frequency of AEs [ Time Frame: From the time of informed consent, for approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
    For Phase 2

  19. To evaluate the concordance of prior molecular profiling that detected a RET alteration within the subject's tumor with diagnostic tests being evaluated by the Sponsor [ Time Frame: 6 months ]
    For Phase 2

  20. Phase 2: Post-operative stage on patients treated with LOXO-292. [ Time Frame: Up to 3 years ]
    Tumor stage is described according to the TNM Classification of malignant tumors of the Union for International Cancer Control (UICC).

  21. Phase 2: Surgical margin status in patients treated with LOXO-292. [ Time Frame: Up to 3 years ]
    Tumor margins after surgery are classified into four groups using the International Cancer Control (UICC)-R classification and the Intergroup Rhabdomyosarcoma Staging (IRS) systems: 1) Complete tumor resection with histologically free margins, 2) Macroscopic resection but invaded margins on histology, 3)Macroscopic residual tumor and 4) Distant metastatic tumor.

  22. Descriptive analysis of pretreatment surgical plan [ Time Frame: Up to 3 years ]
    For Phase 2

  23. Descriptive analysis of post-treatment plans [ Time Frame: Up to 3 years ]
    For Phase 2



Information from the National Library of Medicine

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Ages Eligible for Study:   6 Months to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Advanced or metastatic solid or primary CNS tumor which has failed standard of care therapies
  • Evidence of an activating RET gene alteration in the tumor and/ or blood
  • Measurable or non-measurable disease
  • Karnofsky (patients 16 years and older) or Lansky (patients younger than 16) performance score of at least 50.
  • Patient with primary CNS tumors or cerebral metastases must be neurologically stable for 7 days prior and must not have required increasing doses of steroids within the last 7 days.
  • Adequate hematologic, hepatic and renal function.
  • Ability to receive study drug therapy orally or via gastric access
  • Willingness of men and women of reproductive potential to observe conventional and effective birth control

Exclusion Criteria:

  • Major surgery within 4 weeks prior to planned start of LOXO-292.
  • Clinically significant, uncontrolled cardiac, cardiovascular disease or history of myocardial infarction within 6 months prior to planned start of LOXO-292.
  • Active uncontrolled systemic bacterial, viral, fungal or parasitic infection.
  • Clinically significant active malabsorption syndrome.
  • Pregnancy or lactation
  • Uncontrolled symptomatic hyperthyroidism or hypothyroidism (i.e. the patient required a modification to current thyroid medication in the 7 days before start of LOXO-292).
  • Uncontrolled symptomatic hypercalcemia or hypocalcemia.
  • Current treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers.
  • Known hypersensitivity to any of the components of the investigational agent, LOXO-292 or Ora-Sweet® SF and OraPlus®, for patients who will receive LOXO-292 suspension.
  • Current treatment with proton pump inhibitors.
  • Prior treatment with a selective RET inhibitor(s) (including investigational selective RET inhibitor[s]).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03899792


Contacts
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Contact: Patient Advocacy 855-RET-4-292 (855-738-4292) clinicaltrials@loxooncology.com

Locations
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United States, California
Children's Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90027
United States, Massachusetts
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
United States, Tennessee
St. Jude Children's Research Hospital, Inc. Recruiting
Memphis, Tennessee, United States, 38105
United States, Texas
University of Texas, Southwestern Medical Center Recruiting
Dallas, Texas, United States, 75235
Texas Children's Hospital Recruiting
Houston, Texas, United States, 77030
United States, Washington
Seattle Children's Hospital Recruiting
Seattle, Washington, United States, 98105
Sponsors and Collaborators
Loxo Oncology, Inc.
Investigators
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Study Director: Elizabeth Olek, DO, MPH Loxo Oncology

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Responsible Party: Loxo Oncology, Inc.
ClinicalTrials.gov Identifier: NCT03899792     History of Changes
Other Study ID Numbers: LOXO-RET-18036
2019‐000212‐28 ( EudraCT Number )
First Posted: April 2, 2019    Key Record Dates
Last Update Posted: October 4, 2019
Last Verified: October 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Loxo Oncology, Inc.:
SPECC1L-RET
Loxo
LOXO-292
KIF5B-RET
M918T
CCDC6-RET
RET-PTC1
NCOA4-RET
RET-PTC
RET-PTC3
RET-PTC4
PRKAR1A-RET
RET-PTC2
GOLGA5-RET
RET-PTC5
ERC1-RET
KTN1-RET
RET-PTC8
HOOK3-RET
PCM1-RET
TRIM24-RET
RET-PTC6
TRIM27-RET
TRIM33-RET
RET-PTC7
AKAP13-RET
FKBP15-RET
TBL1XR1-RET
BCR-RET
FGRF1OP-RET
Additional relevant MeSH terms:
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Sarcoma
Thyroid Neoplasms
Nervous System Neoplasms
Central Nervous System Neoplasms
Thyroid Cancer, Papillary
Fibrosarcoma
Myofibromatosis
Thyroid Diseases
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Endocrine System Diseases
Endocrine Gland Neoplasms
Neoplasms by Site
Head and Neck Neoplasms
Nervous System Diseases
Adenocarcinoma, Papillary
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms, Fibrous Tissue
Neoplasms, Connective Tissue