Alectinib-induced Endocrine Toxicity (TOSS-ALK)

Alectinib-induced Endocrine Toxicity in Patients With ALK-positive Advanced NSCLC: an Onservational Study

The experimental Cohort A (male ALK+ ANSCLC patients receiving alectinib), the control Cohort B (female ALK+ ANSCLC patients receiving alectinib) and control Cohort C (male NON-ALK ANSCLC patients) were prospectively evaluated for full hormone assessment of androgen deficiency, AT 8 weeks after treatment start and in case of reported suspected symptoms. Patients with major sexual dysfunctions were referred to endocrinologist.

Study Overview

• Status: Completed
• Conditions: NSCLC Stage IV
• Intervention / Treatment: Drug: Alectinib 150 MG [Alecensa]

Detailed Description

Male patients (Cohorts A-C). After 8 weeks from treatment start (T1), as the same time of initial endocrine evaluation, we assessed symptoms of androgen deficiency by using the Androgen Deficiency in Aging Males (ADAM) questionnaire (Supplementary, SD1), a validated screening assessment of hypogonadism in adult males [15]. Next, the questionnaire was collected every 12 weeks during the routine clinic visits up to three years (if considered clinically appropriated). The response to the questionnaire was considered consistent with possible hypogonadism (i.e. positive), if the patient reported at least one major symptom (loss of libido and/or impotence; questions 1 and 7) or at least three minor symptoms. In case of suspected hypogonadism at ADAM questionnaire, hormonal tests were again performed and the patient was referred to Andrology Unit of the Endocrinology Departement in case of abnormal results. Andrology visit included physical examination, testicular and scrotum ultrasound, medical history and hormonal tests reviewing; when testosterone replacement and/or drugs for erectile dysfunction were prescribed, the overall effectiveness on symptoms of hypogonadism (improved/not improved) was assessed by the andrologist and checked at next oncologic visits.

Female patients (Cohort B). After 8 weeks from treatment start (T1), as the same time of initial endocrine assessment, we assessed symptoms of sexual dysfunctions, according to menopausal status, by using the EORTC QLQ - BR23 and FACT-B (Version 4) questionnaires. In case of clinically significant gynaecological symptoms and/or abnormal results of sexual hormones axis in relation to menopausal status, the patients were referred to multidisciplinary evaluation by an endocrinologist and a gynaecologist. Multidisciplinary evaluation included physical and gynaecological examination, pelvic ultrasound, medical history and hormonal tests reviewing; diagnosis and treatment of endocrine/gynaecological dysfunction and prescribed treatment/intervention were reported in medical history and checked at next oncologic visits

• Study Type: Observational
• Enrollment (Actual): 98

Contacts and Locations

Study Locations

• Italy
  • Rome, Italy, 00168
    • Fondazione Policlinico Gemelli IRCCS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

TOSS-ALK is single-Institution observational prospective sex-based trial aimed to assess endocrine toxicity in ALK+ advanced/metastatic ANSCLC male patients treated with first-line alectinib (Cohort A). As control cohorts, we included female ALK+ ANSCLC patients (Cohort B) and male patients with NON-ALK+ NSCLC who are receiving active treatment (ACT) according to tumour molecular profiling (Cohort C).

Description

Inclusion Criteria:

1. Histologically or cytologically confirmed advanced NSCLC (ANSCLC) For ALK+ NSCLC (Cohorts A-B) 1a. ALK-rearrangement confirmed by NGS and/or VENTANA ALK (D5F3) immunoistochemical assay 1b. Treatment naïve patients candidate to treatment with alectinib oral at standard dose of 600 mg twice daily
2. Patient aged 18 to 70 years
3. To be sexually active at time of enrolment
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
5. Written informed consent

Exclusion Criteria:

1. History of endocrine disorders, excepting for controlled hypothyroidism (surgical or non-surgical) treated with replacement levothyroxine since at least 2 years
2. Any cancer-related or medical condition that would interfere with the patient reported outcomes or laboratory assessment. Examples include, but are not limited to:

2a. Cancer-related conditions that may preclude/undermine sexual activity (e.g. leptomeningeal carcinomatosis, pathological vertebral fractures, gonadic metastases, unstable spinal cord compression, uncontrolled neurological symptoms, surgical complications)

2b. History of chronic liver disease or hormonal replacement therapy (e.g. ADT for prostatic cancer)

2c. Participants who not adequately recovered from previous confirmed chemotherapy-induced gonadotoxicity (e.g. cisplatin)

2d. Chronic use of drugs with known effect on male sexuality, including opiates, anxiolytics, antidepressants, mood stabilizers, beta blockers (e.g. atenolol) and high dose diuretics

2e. Psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study

2f. Major psychological disorder and/or high distress level that would interfere with sexual function and the participant's ability to cooperate with the requirements of the study

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Cohort A; Male ALK-positive ANSCLC patients receiving first-line treatment with alectinib	Drug: Alectinib 150 MG [Alecensa]; First line treatment for cohorts A and B; Other Names: Alecensa
Cohort B; Female ALK-positive ANSCLC patients receiving first-line treatment with alectinib	Drug: Alectinib 150 MG [Alecensa]; First line treatment for cohorts A and B; Other Names: Alecensa
Cohort C; Male ALK-negative ANSCLC patients receiving first-line treatment according to molecular profiling

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of endocrine toxicity in overall ALK-positive	Percentege of endocrine alterations among patients included in Cohort A and B	Time from treatment start until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years
Incidence of symptomatic hypogonadism in male ANSCLC patients	Percentage of endocrine alterations and/or clinical sexual dysfuctions among male patients included in Cohort A and C	Time from treatment start until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years

Collaborators and Investigators

• Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Study record dates

Study Major Dates

• Study Start (Actual): October 12, 2018
• Primary Completion (Actual): October 30, 2023
• Study Completion (Actual): October 30, 2023

Study Registration Dates

• First Submitted: March 25, 2024
• First Submitted That Met QC Criteria: March 25, 2024
• First Posted (Actual): April 1, 2024

Study Record Updates

• Last Update Posted (Actual): April 1, 2024
• Last Update Submitted That Met QC Criteria: March 25, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; Alectinib
• Other Study ID Numbers: 4806

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No