A Phase 1/2 study on the effects of LOXO-292 (study drug) in patients with advanced solid tumors.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Loxo Oncology Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

22 Sep 2017 → ongoing

Decision date (initial)

2024-04-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Loxo Oncology, Inc.

External identifiers

EU CT number

2023-507702-13-00

EudraCT number

2017-000800-59

WHO UTN

U1111-1302-4546

ClinicalTrials.gov

NCT03157128

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Pharmacokinetic, Safety, Efficacy

Primary Objective (Phase 1) - To determine the MTD/recommended Phase 2 dose (RP2D) of selpercatinib.
Primary Objective (Phase 2) - To assess, for each Phase 2 expansion cohort, the anti-tumor activity of selpercatinib by determining ORR using RECIST 1.1 or RANO, as appropriate to tumor type, as assessed by independent review committee (IRC).

Conditions and MedDRA coding

Male or female patients age 12 years or older with a locally advanced or metastatic solid tumor with evidence of a RET gene alteration in tumor and/or blood.

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 20

1. 1. 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.
2. 10. Phase 1: Adequate hepatic function, defined as: - ALT and AST ≤ 2.5 ULN or ≤ 5 ULN with documented liver involvement (such as liver metastasis or a primary biliary tumor), and - Total bilirubin ≤ 1.5 ULN or ≤ 3 ULN with documented liver involvement (patients with Gilbert's Disease may be enrolled with prior Sponsor approval).
3. 11. Phase 1: Adequate renal function, with estimated glomerular filtration rate ≥ 30 mL/minute (up to 6 patients with an estimated glomerular filtration rate (eGFR) ≥ 15 and < 30 will be allowed to enroll with Sponsor approval).
4. 12. Phase 1: Ability to swallow capsules and comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation.
5. 13. Phase 1: Willingness of men and women of reproductive potential to observe conventional and effective birth control for the duration of treatment and for 1 month following the last dose of study treatment.
6. 2. Phase 1: Prior MKIs with anti-RET activity are allowed.
7. 3. Phase 1: 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.
8. 4. Phase 1: Measurable or non-measurable disease as determined by RECIST 1.1 or RANO as appropriate to tumor type.
9. 5. Phase 1: At least 18 years of age. - For countries and sites where approved, patients as young as 12 years of age may be enrolled.
10. 6. Phase 1: Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 (age ≥ 16 years) or Lansky Performance Score (LPS) ≥ 40% (age < 16 years) with no sudden deterioration 2 weeks prior to the first dose of study treatment.
11. 7. Phase 1: Life expectancy of at least 3 months.
12. 8. Phase 1: Archived tumor tissue sample available.
13. 9. Phase 1: Adequate hematologic status, defined as: - Absolute neutrophil count (ANC) ≥ 1.0.10^9/L not requiring growth factor support for at least 7 days prior to treatment, and - Platelet count ≥ 75.10^9/L not requiring transfusion support for at least 7 days prior to treatment, and - Hb ≥ 9 g/dL not requiring transfusion support or erythropoietin for at least 7 days prior to treatment.
14. 1. Phase 2: Cohorts 1 and 3: failed or intolerant to standard of care. Cohorts 2 and 4 without prior standard first line therapy.
15. 2. Phase 2: Cohorts 1-4: enrollment will be restricted to patients with evidence of a RET gene alteration in tumor (i.e., not just blood) as defined in Table 3.
16. 3. Phase 2: However, a positive germline DNA test for a RET gene mutation as defined in Table 3 3 is acceptable in the absence of tumor tissue testing for patients with MTC.
17. 4. Phase 2: 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 (unless PD for the irradiated lesion[s] has been radiographically documented).
18. 5. Part 2: Cohort 4: radiographic PD within the previous 14 months.
19. 6. Phase 2: Cohort 6: Patients who otherwise are eligible for Cohorts 1-5 who discontinued another RET inhibitor may be eligible with prior Sponsor approval. Note: Examples of RET inhibitors may include TPX0046, pralsetinib (BLU667), or BOS172739.
20. 7. Part 2: Cohort 5: Patients who otherwise are eligible for: - Cohorts 1-4 without measurable disease; - MTC not meeting the requirements for Cohorts 3 or 4; - 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.

Exclusion criteria 15

1. 1. Phase 2 Cohorts 1-4: an additional validated oncogenic driver that could cause resistance to selpercatinib treatment. See Appendix C (Table 11 3) for examples.
2. 2. Cohorts 1 to 5: Prior treatment with a selective RET inhibitor(s) (including investigational selective RET inhibitor[s]).
3. 3. 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 selpercatinib. In addition, no concurrent investigational anti-cancer therapy is permitted.
4. 4. Major surgery (excluding placement of vascular access) within 4 weeks prior to planned start of selpercatinib.
5. 5. Radiotherapy with a limited field of radiation for palliation within 1 week of the first dose of study treatment, 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.
6. 6. 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.
7. 7. Symptomatic primary CNS tumor, metastases, leptomeningeal carcinomatosis, or untreated spinal cord compression. Exception: 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).
8. 8. Clinically significant active cardiovascular disease or history of myocardial infarction within 6 months prior to planned start of selpercatinib or prolongation of the QT interval corrected for heart rate using Fridericia's formula (QTcF) interval > 470 msec during Screening. Correction of suspected drug-induced QTcF prolongation may be attempted at the Investigator's discretion if clinically safe to do so.
9. 9. Active uncontrolled systemic bacterial, viral, or fungal infection or serious ongoing intercurrent illness, such as hypertension or diabetes, despite optimal treatment. Screening for chronic conditions is not required.
10. 10. Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the study drug.
11. 11. Uncontrolled symptomatic hyperthyroidism or hypothyroidism.
12. 12. Uncontrolled symptomatic hypercalcemia or hypocalcemia.
13. 13. Pregnancy or lactation.
14. 14. Active second malignancy other than minor treatment of indolent cancers.
15. 15. History of hypersensitivity to any of the study drug capsule components, or any of the liquid suspension components (for patients that cannot swallow capsules).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. 1. Phase 1: MTD/RP2D.
2. 2. Phase 2: ORR based on RECIST 1.1 or RANO, as appropriate to tumor type, assessed by IRC.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Loxo Oncology Inc.

Sponsor organisation

Loxo Oncology Inc.

Address

281 Tresser Boulevard Floor 9th

City

Stamford

Postcode

06901-3238

Country

United States

Scientific contact point

Organisation

Loxo Oncology Inc.

Contact name

Eli Lilly & Co.

Public contact point

Organisation

Loxo Oncology Inc.

Contact name

Eli Lilly & Co.

Third parties 6

Locations

5 EU/EEA countries · 12 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 62 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications