Ensayos clínicos

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. Refer to Appendix A for examples of MKIs with anti-RET activity. The specific agent(s), duration of treatment, clinical benefit, and reason for discontinuation (e.g., PD, drug toxicity, or intolerance) should be documented for all kinase inhibitors the patient has been exposed to.
• A RET gene alteration is not required initially. Once adequate PK exposure is achieved (see below), evidence of RET gene alteration in tumor and/or blood is required (e.g., gene rearrangement and/or mutation, excluding synonymous, frameshift, or nonsense mutations) as identified through molecular assays, as performed for clinical evaluation. The RET alteration result should be generated from a laboratory with CLIA, ISO/IEC, CAP or other similar certification. The Sponsor should be contacted to discuss test results from labs where such certification is not clearly demonstrated to determine eligibility.
• Notes:
  • During Phase 1, a RET gene alteration is not required initially. The Sponsor’s preclinical data indicates that a LOXO-292 plasma level of 70 ng/mL is equivalent to the IC50 for RET (corrected for human plasma protein binding). Therefore, once a dose level is achieved that: (1) is associated with a DLT rate of < 33%; (2) is deemed safe by the SRC; and (3) is associated with a Cmin of > 70 ng/mL at steady state in ≥ 70% of patients in the same dosing cohort (e.g., 3/3, 3/4, 4/5, 5/6 patients, etc.), enrollment to subsequent dose levels during Phase 1 will be restricted to patients with: (1) RET fusion-positive solid tumors; (2) MTC; (3) an advanced solid tumor that harbors a RET gene alteration (excluding synonymous, frameshift, or nonsense mutations); or (4) with prior Sponsor approval, an advanced solid tumor with other evidence of RET activation (refer to Section 4).
  • A positive germline test for a RET mutation is acceptable for patients with MTC.
  • Local testing in a CLIA, ISO/IEC, CAP, or other similar certified laboratory is sufficient.
  • In all cases, an anonymized/redacted Molecular Pathology Report or other report(s) describing tumor RET (and other) alteration analysis should be submitted to the Sponsor or designee during/prior to eligibility.
• Measurable or non-measurable disease as determined by RECIST 1.1 or RANO as appropriate to tumor type.
• At least 18 years of age.
  • For countries and sites where approved, patients as young as 12 years of age may be enrolled. (Canada is excluded from enrolling minors [patients under 18 years of age] into the study).
• 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.
• Life expectancy of at least 3 months.
• Archived tumor tissue sample available.
• Notes:
  • Patients who do not have adequate archival tumor tissue available (refer to specific archival tissue requirements in Section 7.8.5.1) should undergo a fresh tumor biopsy, if it is considered safe to perform, prior to treatment (requirement may be waived with Sponsor approval).
  • If archived tumor tissue was obtained prior to progression on the last MKI with anti-RET activity, the patient should undergo a fresh tumor biopsy, if it is considered safe to perform prior to treatment (optional).
• Adequate hematologic status, defined as:
  • Absolute neutrophil count (ANC) ≥ 1.0 × 109/L not requiring growth factor support for at least 7 days prior to treatment, and
  • Platelet count ≥ 75 × 109/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.
• Adequate hepatic function, defined as:
  • ALT and AST ≤ 2.5 × the upper limit of normal (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).
• 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 mL/minute will be allowed to enroll with Sponsor approval).
• Ability to swallow capsules and comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation. If the liquid formulation is widely available, this requirement may be waived with Sponsor approval.
• Willingness of men and women of reproductive potential to observe conventional and effective birth control for the duration of treatment and for 3 months following the last dose of study treatment; this may include barrier methods such as condoms or diaphragms with spermicidal gel.
• Notes:
  • A postmenopausal woman will be defined as having no menses for 12 months without an alternative medical cause. Male sterility will be defined as only men sterilized surgically. For male patients with a pregnant partner, a condom should be used for contraception. For male patients with a non-pregnant female partner of child-bearing potential and woman of child-bearing potential one of the following birth control methods with a failure rate of less than 1% per year when used consistently and correctly are recommended:
    • Combined estrogen and progesterone containing hormonal contraception associated with inhibition of ovulation given orally, intravaginally, or transdermally
    • Progesterone-only hormonal contraception associated with inhibition of ovulation given orally, by injection, or by implant
    • Intrauterine device (IUD)
    • Intrauterine hormone-releasing system (IUS)
    • Bilateral tubal occlusion
    • Vasectomized partner
    • Sexual abstinence
•  Birth control methods unacceptable for this clinical trial are:
  • Periodic abstinence (calendar, symptothermal, or post-ovulation methods)
  • Withdrawal (coitus interruptus)
  • Spermicide only
  • Lactational amenorrhea method

For Phase 2

Inclusion Criteria are the same as for Phase 1, with the following modifications:

• Cohorts 1 and 3: failed or intolerant to standard of care.
• Cohorts 2 and 4: without prior standard-first line therapy.

Exclusion Criteria:

 Phase 1 and Phase 2

• Phase 2 Cohorts 1-4: an additional validated oncogenic driver that could cause resistance to LOXO-292 treatment.
• Cohorts 1-5: prior treatment with a selective RET inhibitor(s) (including investigational selective RET inhibitor[s]).
  • 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 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.
• 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.
  • 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).
  • Note:  During the Phase 2 portion of the study, all prior local treatments for CNS disease (e.g., surgery, whole brain radiation [WBRT], SRS), the start and stop dates for each prior local therapy, the specific lesions treated (if SRS and/or surgery), whether the patient developed intracranial progression after the last prior local treatment, and which lesions progressed since completion of the local therapy must be documented.
• 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 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.
• 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.
• Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the study drug.
• Uncontrolled symptomatic hyperthyroidism or hypothyroidism.
• Uncontrolled symptomatic hypercalcemia or hypocalcemia.
• Current treatment with certain strong CYP3A4 inhibitors or inducers (outlined in Appendix D) and certain prohibited concomitant medications.
• Current treatment with PPIs (refer to Appendix E).
  • Note: Treatment with PPIs must be stopped 1 or more weeks prior to the first dose of LOXO-292.
• Pregnancy or lactation.
• Active second malignancy other than minor treatment of indolent cancers.
• History of hypersensitivity to any of the study drug capsule components.