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NCT03157128 | SNCTP000002813

Eine Studie der Phase 1/2 zu oral verabreichtem LOXO-292 an Patienten mit fortgeschrittenen soliden Tumoren, einschliesslich RET-Fusion-positiver solider Tumoren, medullärem Schilddrüsenkarzinom und anderer Tumoren mit RET-Aktivierung (LIBRETTO-001)

Data source: BASEC (Imported from 16.10.2019), WHO (Imported from 13.10.2019)
Changed: 09.10.2019
Disease category: Anderer Krebs

Brief description of trial (Source of data: BASEC)

Die Studie wird voraussichtlich etwa 28 Monate dauern. Sie wird in zwei Phasen durchgeführt: Dosiseskalation und Dosisexpansion. Die Dosiseskalation läuft noch. In der Schweiz, wird jedoch nur die Dosisexpansion durchgeführt. Auf der Grundlage der Krebsart und vorhergehenden Krebstherapien werden Patienten in eine von fünf Gruppen aufgenommen (sogenannte Expansionskohorten).
Bis zu 870 Personen werden voraussichtlich an der klinischen Studie teilnehmen. In der Schweiz, werden nur Patienten im Alter von 18 Jahren oder älter in der Studie eingeschlossen. Die Studie wird an ungefähr 100 Prüfzentren in den USA, in Europa und Asien durchgeführt.
Die hier beschriebene Studie ist die erste Studie am Menschen zum Prüfmedikament LOXO-292. Prüfmedikament bedeutet, dass LOXO-292 derzeit von keiner Arzneimittel- oder Zulassungsbehörde zugelassen wurde.

Health conditions investigated (Source of data: BASEC)

Patienten mit fortgeschrittenen soliden Tumoren, einschließlich nicht-kleinzelligem Bronchialkarzinom (Non-Small Cell Lung Cancer, NSCLC) mit RET-Fusion, medullärem Schilddrüsenkarzinom und anderer Tumoren mit erhöhter RET-Aktivität.

Health conditions (Source of data: WHO)

Non-Small Cell Lung Cancer;Medullary Thyroid Cancer;Colon Cancer;Any Solid Tumor

Rare disease (Source of data: BASEC)

No

Intervention investigated (e.g. drug, therapy or campaign) (Source of data: BASEC)

LOXO-292 ist ein Tyrosinkinasehemmer, der entwickelt wurde, um ein Protein namens RET so stark wie möglich zu hemmen und andere Signalwege in der Krebszelle zu blockieren. Infolgedessen kann man davon ausgehen, dass LOXO-292 bei Tumoren mit Abweichungen im RET-Gen wirksamer sein könnte. Bei nicht-kleinzelligem Bronchialkarzinom und Schilddrüsenkarzinom treten Abweichungen im RET-Gen am häufigsten auf, aber sie können auch bei anderen Tumorarten vorkommen.

Interventions (Source of data: WHO)

Drug: LOXO-292

Criteria for participation in trial (Source of data: BASEC)

Einschlusskriterien Phase 1:
1. Patienten mit einem lokal fortgeschrittenen oder metastasierten soliden Tumor, die:
• Unter einer Standardtherapie fortgeschritten sind oder die eine Standardtherapie nicht vertragen oder
• Es ist keine Standardtherapie vorhanden oder
• Patienten, die eine Standardtherapie ablehnen oder
• Nach Einschätzung des Prüfarztes für eine Standardtherapie nicht infrage kommen oder diese wahrscheinlich nicht vertragen oder keinen signifikanten klinischen Nutzen daraus ziehen würden.
2. Eine beliebige Anzahl vorheriger MKIs mit Anti-RET-Aktivität ist erlaubt. Beispiele für Multi-Kinase-Inhibitoren (MKIs) mit Anti-RET-Aktivität siehe Appendix A.
3. Nachweis einer RET-Genalteration ist initial nicht gefragt.

Exclusion criteria (Source of data: BASEC)

Ausschlusskriterien für Phase 1 und Phase 2:
1. Phase 2, Kohorte 1-4, das Vorliegen eines zusätzlichen validierten, krebsinduzierenden, genetischen Faktors, der eine Resistenz gegen die LOXO-292-Behandlung verursachen könnte.
2. Phase 2, Kohorte 1-5: vorherige Behandlung mit einem selektiven RET-Inhibitor(en)
3. Behandlung mit einem Prüfpräparat oder einer Krebstherapie innerhalb von 5 Halbwertszeiten oder 2 Wochen (maßgeblich ist der kürzere Zeitraum) vor dem geplanten Beginn von LOXO-292.
4. Größere Operation (mit Ausnahme des Legens eines vaskulären Zugangs) innerhalb von 4 Wochen vor dem geplanten Beginn von LOXO-292.

Inclusion/Exclusion Criteria (Source of data: WHO)


Key Inclusion Criteria:

For Phase 1

- Patients with a locally advanced or metastatic solid tumor who:

- have progressed on or are intolerant to standard therapy, or

- no standard therapy exists, or in the opinion of the Investigator, are not
candidates for or would be unlikely to tolerate or derive significant clinical
benefit from standard therapy, or

- decline standard therapy

- Prior MKIs with anti-RET activity are allowed.

- A RET gene alteration is not required initially. Once adequate PK exposure is
achieved, evidence of RET gene alteration in tumor and/or blood is required as
identified through molecular assays, as performed for clinical evaluation.

- Measurable or non-measurable disease as determined by RECIST 1.1 or RANO as
appropriate to tumor type.

- Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 or Lansky Performance
Score (LPS) = 40% (age < 16 years) with no sudden deterioration 2 weeks prior to the
first dose of study treatment.

- Adequate hematologic, hepatic and renal function.

- Life expectancy of at least 3 months.

For Phase 2

As for phase 1 with the following modifications:

- For Cohorts 1 and 3 Subjects must have received prior standard therapy appropriate for
their tumor type and stage of disease, or in the opinion of the Investigator, would be
unlikely to tolerate or derive clinical benefit from appropriate standard of care
therapy.

- Cohorts 1-4: enrollment will be restricted to patients with evidence of a RET gene
alteration in tumor. However, a positive germline DNA test for a RET gene mutation is
acceptable in the absence of tumor tissue testing for patients with MTC.

- Cohorts 1-4: at least one measurable lesion as defined by RECIST 1.1 or RANO, as
appropriate to tumor type and not previously irradiated.

- Cohort 4: radiographic PD within the previous 14 months.

Note: Patients otherwise eligible for cohort 4 who do not demonstrate radiographic PD
within the previous 14 months may be enrolled to cohort 5 if a compelling rationale is
provided by the investigator and approved by the Sponsor.

- Cohort 5: (up to 150 patients):

- Cohorts 1-4 without measurable disease;

- MTC not meeting the requirements for Cohorts 3 or 4; (a known RET mutation is not
required)

- MTC syndrome spectrum cancers (e.g., MTC, pheochromocytoma), cancers with
neuroendocrine features/differentiation, or poorly differentiated thyroid cancers
with other RET alteration/activation may be allowed with prior Sponsor approval;

- cfDNA positive for a RET gene alteration not known to be present in a tumor
sample.

- Cohort 6: Patients who otherwise are eligible for Cohorts 1-5 who discontinued another
RET inhibitor due to intolerance may be eligible with prior Sponsor approval.

Key Exclusion Criteria (Phase 1 and Phase 2):

- Phase 2 Cohorts 1-4: an additional known oncogenic driver.

- Cohorts 1-5: prior treatment with a selective RET inhibitor

Notes:

Patients otherwise eligible for Cohorts 1-5 who discontinued another selective RET
inhibitor may be eligible for Phase 2 Cohort 6 with prior Sponsor approval.

Notes:

Patients otherwise eligible for Cohorts 1-5 who discontinued another selective RET
inhibitor may be eligible for Phase 2 Cohort 6 with prior Sponsor approval.

Notes:

Patients otherwise eligible for Cohorts 1-5 who discontinued another selective RET
inhibitor may be eligible for Phase 2 Cohort 6 with prior Sponsor approval.

- Investigational agent or anticancer therapy (including chemotherapy, biologic therapy,
immunotherapy, anticancer Chinese medicine or other anticancer herbal remedy) within 5
half-lives or 2 weeks (whichever is shorter) prior to planned start of LOXO-292. In
addition, no concurrent investigational anti-cancer therapy is permitted.

Note:

Potential exception for this exclusion criterion will require a valid scientific
justification and approval from the Sponsor.

- Major surgery (excluding placement of vascular access) within 4 weeks prior to planned
start of LOXO-292.

- Radiotherapy with a limited field of radiation for palliation within 1 week of planned
start of LOXO-292, with the exception of patients receiving radiation to more than 30%
of the bone marrow or with a wide field of radiation, which must be completed at least
4 weeks prior to the first dose of study treatment.

- Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of
starting study treatment with the exception of alopecia and Grade 2, prior
platinum-therapy related neuropathy.

- Symptomatic primary CNS tumor, metastases, leptomeningeal carcinomatosis, or untreated
spinal cord compression. Patients are eligible if neurological symptoms and CNS
imaging are stable and steroid dose is stable for 14 days prior to the first dose of
LOXO-292 and no CNS surgery or radiation has been performed for 28 days, 14 days if
stereotactic radiosurgery [SRS].

- Clinically significant active cardiovascular disease or history of myocardial
infarction within 6 months prior to planned start of LOXO-292 or prolongation of the
QT interval corrected (QTcF) > 470 msec.

- Required treatment with certain strong CYP3A4 inhibitors or inducers and certain
prohibited concomitant medications.

Further information on the trial in WHO primary registry

https://clinicaltrials.gov/show/NCT03157128

Further information on the trial from WHO database (ICTRP)

http://apps.who.int/trialsearch/Trial2.aspx?TrialID=NCT03157128

Further information on trial

Date trial registered

09.05.2017

Incorporation of the first participant

09.05.2017

Recruitment status

Recruiting

Academic title (Source of data: WHO)

A Phase 1/2 Study of Oral LOXO-292 in Patients With Advanced Solid Tumors, Including RET Fusion-Positive Solid Tumors, Medullary Thyroid Cancer, and Other Tumors With RET Activation (LIBRETTO-001)

Type of trial (Source of data: WHO)

Interventional

Design of the trial (Source of data: WHO)

Intervention model: Single Group Assignment. Primary purpose: Treatment. Masking: None (Open Label).

Phase (Source of data: WHO)

Phase 1/Phase 2

Primary end point (Source of data: WHO)

Phase 1: Maximum tolerated dose (MTD);Phase 2: Objective Response Rate;Phase 1: Recommended Phase 2 dose (RP2D)

Secundary end point (Source of data: WHO)

Phase 2: Plasma concentrations of LOXO-292 and PK parameters, including but not limited to AUC0-24, Cmax, and Tmax.;Phase 2: Frequency, severity and relatedness of TEAEs and SAEs, changes in hematology and blood chemistry values, assessments of physical examinations, vital signs and ECGs.;Phase 2: OS;Phase 2: PFS (by IRC and Investigator);Phase 2: CBR (by IRC and Investigator);Phase 2: time to any and best response (by IRC and Investigator);Phase 2: CNS DOR (by IRC);Phase 2: CNS ORR (by IRC);Phase 2: DOR (by IRC and Investigator);Phase 2: best change in tumor size from baseline (by IRC and Investigator);Phase 2: ORR (by Investigator);Phase 1: ORR based on RECIST 1.1 or RANO, as appropriate to tumor type.;Phase 1: Plasma concentration of LOXO-292 and PK parameters, including but not limited toarea under the curve from time 0 to 24 hours (AUC0-24), maximum drug concentration (Cmax), time to maximum plasma concentration (Tmax), and degree of accumulation.;Phase 1: Frequency, severity, and relatedness of TEAEs and serious adverse events (SAEs), changes in hematology and blood chemistry values, assessments of physical examinations, vital signs, and electrocardiograms (ECGs).

Contact information (Source of data: WHO)

Please refer to primary and secondary sponsors

Trial sites

Trial sites in Switzerland (Source of data: BASEC)

Luzern

Countries (Source of data: WHO)

Australia, Canada, Denmark, France, Germany, Hong Kong, Israel, Italy, Japan, Korea, Republic of, Singapore, Spain, Switzerland, Taiwan, United Kingdom, United States

Contact for further information on the trial

Details of contact in Switzerland (Source of data: BASEC)

Prof. Dr. med. Oliver Gautschi
+41 41 205 58 60
oliver.gautschi@luks.ch

Contact for general information (Source of data: WHO)

S. Michael Rothenberg, MD, PhD;Patient Advocacy
Loxo Oncology Medical Monitor, VP of R&D
855-RET-4-292 (855-738-4292)
clinicaltrials@loxooncology.com

Contact for scientific information (Source of data: WHO)

S. Michael Rothenberg, MD, PhD;Patient Advocacy
Loxo Oncology Medical Monitor, VP of R&D
855-RET-4-292 (855-738-4292)
clinicaltrials@loxooncology.com

Principal Sponsor/Investigator

Principal sponsor (Source of data: WHO)

Loxo Oncology, Inc.

Further trial identification numbers

BASEC ID (Source of data: BASEC)

2017-02259

Secondary ID (Source of data: WHO)

2017-000800-59;LOXO-RET-17001