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Cola

Phase 1 - Multiple doses of LOXO-292 (selpercatinib) Phase 2 - The maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D)

LOXO-292

There may be multiple sites in this clinical trial. 1-877-CTLILLY (1-877-285-4559) or

Nina Karlin

Erminia Massarelli

Lyudmila Bazhenova

Jonathan Goldman

Michael Demeure

Misako Nagasaka

Hyunseok Kang

Minggui Pan

Jennifer Suga

Gerald Falchook

Frederick Wilson

Benjamin Levy

Victor Bernet

Luis Raez

Conor Steuer

Christine Bestvina

Marc Matrana

Ranee Mehra

Lori Wirth

Jacob Sands

Francis Worden

Nehal Lakhani

John Columbus Morris

Saiama Waqar

Fadi Braiteh

Grace Dy

Vamsidhar Velcheti

Alexander Drilon

Jared Weiss

Nathan Pennell

Vineeth Sukrithan

Shivaani Kummar

Devraj Basu

Marcia Brose

Jordan Berlin

Tian Zhang

Vivek Subbiah

Wallace Akerley

Alexander Spira

Mark Burkard

bruce robinson

Benjamin Solomon

Janessa Laskin

Kristoffer Rohrberg

Jacques Medioni

Antoine Italiano

Philippe Cassier

Pascale Tomasini

Diego Tosi

Benjamin Besse

Barbara Deschler-Baier

Jürgen Wolf

Herbert Loong

Talia Golan

Nir Peled

Julia Dudnik

Hovav Nechushtan

Filippo De Braud

Masahiro Morise

Koichi Goto

Jun Sakakibara

Miyako Satouchi

Shinji Takeuchi

Tsutomu Iwasa

Hirotsugu Kenmotsu

YUICHIRO OHE

Makoto Nishio

Tomohiro Sakamoto

Ryo Toyozawa

Kadoaki Ohashi

Haruko Daga

Ji-Youn Han

Yu Jung Kim

Dae Ho Lee

Se Hoon Lee

Byoung Chul Cho

Shao Weng Daniel Tan

Elena Garralda Cabanas

Victor Moreno

Maria Jose de Miguel Luken

Oliver Gautschi

Kuo-Hsuan Hsu

Chih-Hsin Yang

Anna Minchom

Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)

This is an open-label, first-in-human study designed to evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity of selpercatinib (also known as LOXO-292) administered orally to participants with advanced solid tumors, including rearranged during transfection (RET)-fusion-positive solid tumors, medullary thyroid cancer (MTC) and other tumors with RET activation.

This is an open-label, multi-center Phase 1/2 study in participants with advanced solid tumors, including RET fusion-positive solid tumors, MTC, and other tumors with RET activation. The trial will be conducted in 2 parts: Phase 1 (dose escalation - completed) and phase 2 (dose expansion). Participants with advanced cancer are eligible if they have progressed on or are intolerant to available standard therapies, or no standard or available curative therapy exists, or in the opinion of the Investigator, they would be unlikely to tolerate or derive significant clinical benefit from appropriate standard of care therapy, or they declined standard therapy. A dose of 160 milligrams (mg) twice a day (BID) has been selected as the recommended phase 2 dose (RP2D). Approximately 875 participants with advanced solid tumors harboring a RET gene alteration in tumor and/or blood will be enrolled to one of seven phase 2 cohorts:

* Cohort 1: Advanced RET fusion positive solid tumor other than NSCLC or thyroid cancer for participants who progressed on or intolerant to first line therapy (open)
* Cohort 2: Advanced RET fusion positive solid tumor other than NSCLC or thyroid cancer for treatment naïve participants (open)
* Cohort 3: Advanced RET-mutant MTC participants who progressed on or intolerant to first line therapy (closed)
* Cohort 4: Advanced RET-mutant MTC participants who are treatment naïve (closed)
* Cohort 5: Advanced RET-altered solid tumor for participants other than NSCLC or thyroid cancer and RET-mutant MEN2 spectrum tumors (e.g. pheochromocytoma) otherwise ineligible for cohorts 1-4. See details in inclusion/exclusion criteria (open)
* Cohort 6: Participants otherwise eligible for Cohorts 1-5 who discontinued another RET inhibitor due to intolerance may be eligible with prior Sponsor approval (closed)
* Cohort 7: RET fusion positive early-stage non-small cell lung cancer (NSCLC) participants who are candidates for definitive surgery. Participants will receive selpercatinib in a neoadjuvant and adjuvant setting. Participants will be followed for disease recurrence for up to 5 years from the date of surgery (closed)

A Study of Selpercatinib (LOXO-292) in Participants With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRETTO-001)

A Phase 1/2 Study of Oral Selpercatinib (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)

Incidence rate and category of dose limiting toxicities (DLTs) during the first 28-day cycle of LOXO-292 (selpercatinib) treatment

As assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Response Assessment in Neuro-Oncology (RANO), as appropriate to tumor type, as assessed by independent review committee (IRC)

Phase 1: Number of Participants with a TRAE(s)

Phase 1: Number of Participants with an Abnormal Laboratory or Physical Exam Result(s)

Phase 1: ORR based on RECIST 1.1 or RANO, as Appropriate to Tumor Type

Phase 2: Best Change in Tumor Size from Baseline (by IRC and Investigator)

Phase 2: Time to Any and Best Response (by IRC and Investigator)

Phase 2: Percentage of Participants with any SAE(s)

Phase 1 and 2: PK: AUC of LOXO-292 (Selpercatinib)

Phase 1 and 2: PK: Cmax of LOXO-292 (Selpercatinib)

Eli Lilly and Company

Loxo Oncology, Inc.

All patients will undergo both of the following interventions:

Lancet blood sampling Standard intravenous blood sampling

Blood samples will be obtained using a finger-prick (lancet) technique.

Lancet blood sampling

Blood samples will be obtained using a standard intravenous technique.

Standard intravenous blood sampling

James W Scuffham, PhD

Recently published European guidance recommends the evaluation of the radiation dose to the bone marrow in patients undergoing radioiodine therapy for thyroid cancer. The methods described in these guidelines require serial blood samples to be taken from the patient, followed by a sophisticated analysis to determine the radiation dose. However, radiation risk assessments carried out locally have indicated that a relatively high radiation exposure will be received by the operator taking the blood samples, which may prohibit this procedure being carried out routinely.

The radiation dose to the operator will be lowered if the duration of the blood sampling procedure were reduced. The investigators hypothesize that the use of a lancet and pipette to collect blood from the finger tip will greatly reduce the time spent in proximity to the patient, significantly reducing the operator exposure and allowing this procedure to be performed routinely. The proposed method is also less invasive for the patient compared to the intravenous sampling recommended in the guidelines. A proof-of-principal pilot project using radioiodine diluted to the expected concentration in blood has indicated that using very small volumes of blood (such as from a lancet) does not compromise the accuracy of the dosimetry measurement when compared to large-volume standard blood samples.

The primary aim of this study is to investigate whether sampling a small volume of blood using a lancet and pipette can replace standard intravenous blood samples for bone marrow dosimetry in patients undergoing radioiodine treatment for thyroid cancer. Statistical tests will determine whether there is a significant difference between the doses calculated using each blood sampling method. In addition, the investigators will measure the radiation exposure received by the operator during each procedure using Electronic Portable Dosimeters. The results of these measurements will be used to quantify the reduction in operator radiation exposure afforded by the new technique.

Recruitment:

Patients will be recruited to the trial from the pool of routine referrals for this therapy. Potential participants will receive an information leaflet via the post several weeks in advance of attendance at clinic. Patients will have the opportunity to telephone the study team during this time to answer any questions. Patients who are interested in participating will have the procedure further explained verbally by a physicist on the study team upon attending for therapy. The patient will then have time to consider whether or not to participate in the study. Written consent will be sought before commencing the therapy.

Procedures:

In light of the recent guidelines, the proposed new clinical protocol will include blood samples taken from the patient during the in-patient stay. On the day of treatment, blood samples will be taken at 2h and 6h after radioiodine administration, at the same time as the clearance measurements. Thereafter, a blood sample will be taken from the patient once per day, at the same time as one of the clearance measurements. In addition, a further blood sample will be taken when the patient attends for whole-body and SPECT/CT scans. These blood samples will then be analysed in the laboratory using standard radiation measurement procedures to determine the blood dose according to the European guidelines.

This study will involve the patient having blood samples taken by two different methods at each of the time points described above. In the first method, a butterfly needle will be used to gain intravenous access at the antecubital fossa, and a heparinised vacutainer will be used to collect a 4ml blood sample. The needle will then be removed and the venepuncture site dressed with a plaster. In the second method, a single-use safety lancet will be used to puncture the skin on the finger, and a small pipette used to collect a small quantity of blood. The entire pipette will be transferred to a sample tube for later processing. The puncture site on the finger will then be dressed with a small plaster. The exact start and end times for each sample will be recorded using a radio-controlled standard clock.

While carrying out blood sampling, the operator will wear an electronic portable dosimeter (EPD) to measure radiation exposure. This device will be positioned on the operator's chest to reflect the whole body dose received, and will be configured to record the radiation dose as a function of time during the procedure. After the procedure, the data from the EPD will be downloaded and split into two segments representing each blood sampling procedure, using the recorded timing information. Each segment will then be integrated to give the total radiation exposure received by the operator for each procedure. At the end of the treatment, patients will be asked which of the two blood sampling methods were the most tolerable.

Each sample will be labelled with the patient identification number, the date, time and radioisotope (I-131). To minimise the risk of spills, the samples will be transferred to a tray and moved to the Nuclear Medicine Department using a trolley. Sample manipulations will be carried out in the low level counting laboratory in the Nuclear Medicine Department. Three 1ml aliquots of whole blood will be removed from each vacutainer and transferred to appropriately labelled sample containers using an Eppendorf pipette. The volume of the samples collected by pipette will be determined by measuring the weight of the sample and subtracting the previously determined combined weight of the empty pipette and sample tube. Once all the blood samples have been collected and processed, measurements will be taken in an automated gamma counter to determine the concentration of radioiodine. The counting time for the pipette samples will be increased compared to the intravenous samples, in order to ensure the final dosimetry calculations are not influenced by the statistical uncertainty in the measured counts from the smaller volume samples. The resulting data will then be used in the detailed dosimetry calculations, in accordance with the published European guidelines.

Sample Size:

There is no published data available on the intra-patient variation of bone marrow dose using either of the two proposed blood sampling methods. Without knowledge of the expected variances of the measurements in question, accurate sample size calculations are not possible prior to commencing the study. A sample size of 35 patients will be used in this pilot study - this sample size was chosen based on the number of patients seen in the department for this therapy. Recruiting a sample size of 35 patients is achievable within a 2 year time frame. However, the study will be stopped early if the total annual radiation exposure to the operators, combined with the total radiation exposure due to normal clinical workload, is likely to exceed the annual UK dose constraint of 2mSv for whole body radiation exposure (The Ionising Radiations Regulations 1999, SI 1999/3232).

Data Analysis:

Using the measured concentrations of radioiodine in the blood samples, the radiation dose to the bone marrow of each participant will be calculated following the methods described in European guidance (Luster et al, Eur J Nucl Med Mol Imaging 35(10) 1941 2008). This calculation will be performed for each of the two blood sampling methods, creating paired measurements of the same variable for each participant. The statistical significance of the percentage difference in bone marrow dose calculated from each blood sampling method will then be assessed using a Wilcoxon matched pairs test with the null hypothesis that there is no difference in the calculated bone marrow doses. This study has 80% power to demonstrate at the 5% level of statistical significance a difference of no less than 5% between the mean values for the two bone marrow doses. Therefore statistical analysis of the differences has 80% power to show that the null hypothesis that the difference is no greater than 5% is tenable, if indeed this null hypothesis holds true in the population.

The radiation exposure received by the operator during each blood sampling procedure will be measured using an Electronic Portable Dosimeter (EPD) worn on the chest of the operator. The data will be split into two using the known start and end times of each blood sampling procedure. The data will then be integrated over each time period to calculate the total radiation dose for each interval. This will create paired measurements of the same variable for each blood sampling event for each participant. The statistical significance of the percentage difference in the radiation exposures received by the operator during each blood sampling method will then be assessed using a Wilcoxon matched paired test with the null hypothesis that there is no difference between the measured radiation doses. The aim in this case is to show statistically that the null hypothesis of no difference in the mean radiation doses for the 2 techniques is untenable.

Evaluation of Lancet Blood Sampling for Radioiodine Dosimetry in Thyroid Cancer

Royal Surrey County Hospital NHS Foundation Trust

Clinical Scientist

Adenoma

Sarcoma

Fibrosarcoma

Nervous System Neoplasms

Myofibromatosis

Neoplasms, Connective and Soft Tissue

Adenocarcinoma, Papillary

Neoplasms, Fibrous Tissue

Neoplasms, Connective Tissue

Soft Tissue Sarcoma

Infantile Myofibromatosis

Phase 1- Dose Escalation and determination of MTD; multiple dose levels of LOXO-292 to be evaluated; Phase 2 - The MTD/recommended dose from Phase 1

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of Selpercatinib (LOXO-292) in Participants With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRETTO-001)	NCT03157128	Non-Small Cell ... Medullary Thyro... Colon Cancer Any Solid Tumor	LOXO-292	12 Years -	Eli Lilly and Company
Evaluation of Lancet Blood Sampling for Radioiodine Dosimetry in Thyroid Cancer	NCT02658513	Cancer of the T... Cancer of Thyro... Thyroid Cancer Thyroid Carcino...	Lancet blood sa... Standard intrav...	18 Years -	Royal Surrey County Hospital NHS Foundation Trust
A Study of Oral LOXO-292 (Selpercatinib) in Pediatric Participants With Advanced Solid or Primary Central Nervous System (CNS) Tumors	NCT03899792	Medullary Thyro... Infantile Myofi... Infantile Fibro... Papillary Thyro... Soft Tissue Sar...	LOXO-292	6 Months - 21 Years	Eli Lilly and Company
A Study of Oral LOXO-292 (Selpercatinib) in Pediatric Participants With Advanced Solid or Primary Central Nervous System (CNS) Tumors	NCT03899792	Medullary Thyro... Infantile Myofi... Infantile Fibro... Papillary Thyro... Soft Tissue Sar...	LOXO-292	6 Months - 21 Years	Eli Lilly and Company
Evaluation of Lancet Blood Sampling for Radioiodine Dosimetry in Thyroid Cancer	NCT02658513	Cancer of the T... Cancer of Thyro... Thyroid Cancer Thyroid Carcino...	Lancet blood sa... Standard intrav...	18 Years -	Royal Surrey County Hospital NHS Foundation Trust

Spots Global Cancer Trial Database for cancer of thyroid