Adjuvants, Anesthesia

Central Nervous System Depressants

Psychotropic Drugs

All Drugs and Chemicals

Midazolam

Anesthetics

Hypnotics and Sedatives

Anti-Anxiety Agents

Anesthetics, Intravenous

Anesthetics, General

GABA Modulators

Neurotransmitter Agents

* Treatment Period 1: Single administration of midazolam (1 mg) will occur on Study Day 1, after a high fat, high calorie breakfast, followed by PK sampling for 24 hours.
* Treatment Period 2: Single administration of midazolam 1 mg in combination with a single administration of savolitinib (600 mg), after a high fat, high calorie breakfast will occur on Study Day 5 and PK sampling will occur for 24 hours.

Single dose (together with midazolam) on Study Day 5 after a high fat, high calorie breakfast.

Savolitinib

Single dose (alone) on Study Day 1 and single dose (together with savolitinib) on Study Day 5, both after a high fat, high calorie breakfast.

Ronald Goldwater, MD

This study will be an open label, 2 period, fixed sequence study in healthy male subjects, performed at a single study center in the Unites States of America. The purpose of this study is to evaluate the effect of savolitinib on the PK of midazolam, a known cytochrome P450 (CYP) 3A substrate.

This study is designed as an open-label, 2 treatment period, fixed sequence study in healthy male subjects, performed at a single study center.

The study will comprise:

* A screening period of maximum 28 days;
* Two treatment periods:

Treatment Period 1 consists of 5 days (Study Days -1 to 4), starting with admission to the Study Center on Study Day -1, dosing of midazolam alone on Study Day 1 and ending on Study Day 4, after a 3 day washout period.

Treatment Period 2 consists of 2 days (Study Days 5 and 6), with administration of midazolam in combination with savolitinib on Study Day 5. Subjects will be discharged from the Study Center on Study Day 6, after the last PK sample is collected.

* The Follow up Visit will occur at least 14 days (Study Day 19 or after) after the administration of savolitinib in Treatment Period 2.
* Subjects will be admitted to the Study Center on Study Day -1, prior to the evening meal the night before dosing with midazolam alone (Study Day 1) and will stay in house until at least 24 hours after dosing with midazolam in combination with savolitinib (Study Day 5). Subjects will thus be discharged on Study Day 6, after the last PK sample has been collected.

Each subject will be involved in the study between 21 and approximately 48 days.

A Study in Healthy Male Subjects to Understand How Savolitinib When Taken With Midazolam Behaves Inside the Body

An Open Label, 2 Period, Fixed-sequence Study to Assess the Effect of Savolitinib on the Pharmacokinetics of Oral Midazolam (a CYP450 3A Probe) in Healthy Subjects

To assess the effect of savolitinib on the PK of midazolam.

To describe the PK of midazolam in the presence and absence of savolitinib.

To examine the safety and tolerability of midazolam alone and in combination with savolitinib.

Parexel

AstraZeneca

Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Lymphoma

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Lymphosarcoma

Antineoplastic Agents

Micronutrients

Hematinics

Vitamins

Carboplatin

Pemetrexed

Cisplatin

Enzyme Inhibitors

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Folinic Acid

Folate

Vitamin B9

Lorlatinib will be administered by mouth daily plus Pemetrexed by IV infusion every 3 weeks until progression or intolerable toxicity. Platinum-based standard of care chemotherapy by IV infusion will also be given every 3 weeks for the first 4 cycles; carboplatin or cisplatin are the platinum agents that may be selected based on physician discretion. One cycle is defined as 3 weeks.

Participants will receive assigned dose of daily oral lorlatinib continuously for each cycle. Each cycle is 3 weeks.

Lorlatinib

Participants will receive standard of care intravenous Cisplatin or Carboplatin, both chemotherapy medications, on day 1 of each cycle every 3 weeks, for Cycles 1-4. Each cycle is 3 weeks.

Cisplatin or Carboplatin

Participants will receive intravenous Pemetrexed, a chemotherapy medication, on day 1 of each cycle. Each cycle is 3 weeks.

Melissa Johnson, MD

This clinical trial is an open-label, single arm study evaluating the safest dose of lorlatinib in combination with standard of care chemotherapy in participants with metastatic anaplastic lymphoma kinase positive (ALK+) NSCLC who progressed on prior therapy of lorlatinib alone. The main goals of this study are to:

* Evaluate the safety and tolerability of lorlatinib in combination with standard of care chemotherapy.
* Evaluate how well the combination of lorlatinib and standard of care chemotherapy works to treat metastatic anaplastic lymphoma kinase positive (ALK+) NSCLC.
* Evaluate the pharmacokinetics (PK) of lorlatinib when given in combination with standard of care chemotherapy.

Lorlatinib is a kinase inhibitor with in vitro activity against ALK and ROS1. This study's aim is to evaluate the safety of lorlatinib given in combination with platinum-based standard of care chemotherapy in participants with metastatic anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer who progressed after receiving lorlatinib alone.

There will be a lead-in portion for the first six participants treated. Lead-in participants will receive an assigned starting dose of lorlatinib by mouth once daily throughout each cycle. In addition, a platinum-based standard of care chemotherapy regimen, to include carboplatin or cisplatin as well as pemetrexed, will be given intravenously every 3 weeks. A cycle is defined as 3 weeks. After tolerability is confirmed in the lead-in with the first 6 participants on trial, the next 9 participants may begin at an increased starting dose of lorlatinib by mouth once daily. After 4 cycles of oral lorlatinib and intravenous platinum-based standard of care chemotherapy and intravenous pemetrexed, the participant will move into the maintenance regimen. The maintenance regimen will include continuing on daily oral lorlatinib plus intravenous pemetrexed every 3 weeks until disease progression or intolerable toxicity or other reason for discontinuation.

Lorlatinib in Combination With Chemotherapy in Participants With Metastatic Anaplastic Lymphoma Kinase Positive (ALK+) Non-small Cell Lung Cancer (NSCLC) Who Progressed on Single-agent Lorlatinib

Phase II Study of Lorlatinib in Combination With Chemotherapy in Participants With Metastatic Anaplastic Lymphoma Kinase Positive (ALK+) Non-small Cell Lung Cancer (NSCLC) Who Progressed on Single-agent Lorlatinib

Percentage of participants demonstrating a Complete Response (CR) or Partial Response (PR) according to RECIST v1.1 criteria

Pfizer

SCRI Development Innovations, LLC

Gastrointestinal Agents

Famotidine

Antacids

Anti-Ulcer Agents

Histamine

Histamine H2 Antagonists

Histamine phosphate

Histamine Antagonists

Subjects will receive single dose of 600mg savolitinib after a high-fat, high-calorie meal.

Subjects will receive savolitinib 600mg single dose after high-fat, high-calorie meal and after 1.5 hours (Part A) or 5.5 hours (Part B) of famotidine 40mg dose. Famotidine will be administered after an overnight fast of at least 8 hours with approximately 240 mL of water.

Subject will receive savolitinib tablet 600mg orally after a high-fat, high-calorie meal.

Subjects will receive famotidine tablet 40mg orally after an overnight (minimum 8hours) of fasting.

Dr. Ronald Goldwater, MD

This will be an open-label, randomised, 2 part (Part A and Part B), 2 treatment (savolitinib alone or in combination with famotidine), crossover study in healthy, non Japanese, male subjects, performed at a single study centre.

Parts A and B will each have 2 Periods (Period 1 and Period 2) with a crossover design. Part B will be conducted only if results of Part A suggest a clinically meaningful effect of famotidine on savolitinib pharmacokinetics (PK) parameters. In both parts subjects will be randomly assigned 1:1 to receive one of the 2 treatment sequences: savolitinib alone first followed by crossover to the combination treatment of savolitinib+famotidine, or the reverse sequence. Subjects will be admitted for 4 days from one day before the first dose of the study drug and discharged 2 days after. There will be a washout period (no study treatment) of 14 days between the 2 Periods. The essential difference between the 2 parts is that in the combination treatment, famotidine will be administered 2 hours before savolitinib in Part A and 6 hours before savolitinib in Part B. A given subject will receive a total of 1 dose of famotidine and 2 doses of savolitinib during the study.

In this 2 part study, 16 subjects will be randomised in each part to ensure at least 14 evaluable subjects at the end of the last study period. If Part B is conducted, a total of 32 subjects overall are planned to be enrolled in the study. Additional subjects may be enrolled to ensure 14 evaluable subjects in each part if more than 2 subjects are deemed non evaluable.

A Study in Healthy Male Subjects to Understand How Savolitinib Behaves Inside the Body (Pharmacokinetics) When Administered Alone and in Combination With Famotidine

An Open-Label, Randomised, Two Part, Two Treatment Crossover Study in Healthy Subjects to Assess the Pharmacokinetics of Savolitinib When Administered Alone and in Combination With Famotidine

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Cmax ratio of test treatment (savolitinib+famotidine) relative to reference treatment (savolitinib alone) to assess effect of the gastric acid modifier, famotidine, on the PK of savolitinib.

AUC ratio of test treatment (savolitinib+famotidine) relative to reference treatment (savolitinib alone) to assess effect of the gastric acid modifier, famotidine, on the PK of savolitinib.

To investigate the safety and tolerability of savolitinib in combination with famotidine.

To assess the effect of famotidine on the PK of savolitinib metabolites M2 and M3 and to describe the PK parameters and the PK concentration-time profiles for savolitinib, M2, and M3 when savolitinib is administered alone and in combination with famotidine.

AUC(0-t) geometric means ratio of test treatment (savolitinib+famotidine) relative to reference treatment (savolitinib alone) to assess the effect of famotidine on the PK of savolitinib metabolites M2 and M3 and to describe the PK parameters and the PK concentration-time profiles for savolitinib, M2, and M3 when savolitinib is administered alone and in combination with famotidine.

MRCmax ratio of test treatment (savolitinib+famotidine) relative to reference treatment (savolitinib alone) to assess the effect of famotidine on the PK of savolitinib metabolites M2 and M3 and to describe the PK parameters and the PK concentration-time profiles for savolitinib, M2, and M3 when savolitinib is administered alone and in combination with famotidine.

MRAUC ratio of test treatment (savolitinib+famotidine) relative to reference treatment (savolitinib alone) to assess the effect of famotidine on the PK of savolitinib metabolites M2 and M3 and to describe the PK parameters and the PK concentration-time profiles for savolitinib, M2, and M3 when savolitinib is administered alone and in combination with famotidine.

MRAUC(0-t) ratio of test treatment (savolitinib+famotidine) relative to reference treatment (savolitinib alone) to assess the effect of famotidine on the PK of savolitinib metabolites M2 and M3 and to describe the PK parameters and the PK concentration-time profiles for savolitinib, M2, and M3 when savolitinib is administered alone and in combination with famotidine.

tmax ratio of test treatment (savolitinib+famotidine) relative to reference treatment (savolitinib alone) to assess the effect of famotidine on the PK of savolitinib metabolites M2 and M3 and to describe the PK parameters and the PK concentration-time profiles for savolitinib, M2, and M3 when savolitinib is administered alone and in combination with famotidine.

t½,λz ratio of test treatment (savolitinib+famotidine) relative to reference treatment (savolitinib alone) to assess the effect of famotidine on the PK of savolitinib metabolites M2 and M3 and to describe the PK parameters and the PK concentration-time profiles for savolitinib, M2, and M3 when savolitinib is administered alone and in combination with famotidine.

λz ratio of test treatment (savolitinib+famotidine) relative to reference treatment (savolitinib alone) to assess the effect of famotidine on the PK of savolitinib metabolites M2 and M3 and to describe the PK parameters and the PK concentration-time profiles for savolitinib, M2, and M3 when savolitinib is administered alone and in combination with famotidine.

Vz/F ratio of test treatment (savolitinib+famotidine) relative to reference treatment (savolitinib alone) to assess the effect of famotidine on the PK of savolitinib metabolites M2 and M3 and to describe the PK parameters and the PK concentration-time profiles for savolitinib, M2, and M3 when savolitinib is administered alone and in combination with famotidine.

CL/F ratio of test treatment (savolitinib+famotidine) relative to reference treatment (savolitinib alone) to assess the effect of famotidine on the PK of savolitinib metabolites M2 and M3 and to describe the PK parameters and the PK concentration-time profiles for savolitinib, M2, and M3 when savolitinib is administered alone and in combination with famotidine.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study in Healthy Male Subjects to Understand How Savolitinib When Taken With Midazolam Behaves Inside the Body	NCT04187456	Solid Tumors	Savolitinib Midazolam	18 Years - 65 Years	AstraZeneca
Lorlatinib in Combination With Chemotherapy in Participants With Metastatic Anaplastic Lymphoma Kinase Positive (ALK+) Non-small Cell Lung Cancer (NSCLC) Who Progressed on Single-agent Lorlatinib	NCT05948462	Lung Cancer Non-small Cell ...	Lorlatinib Cisplatin or Ca... Pemetrexed	18 Years -	SCRI Development Innovations, LLC
A Study in Healthy Male Subjects to Understand How Savolitinib Behaves Inside the Body (Pharmacokinetics) When Administered Alone and in Combination With Famotidine	NCT04179071	Solid Tumours	Savolitinib Famotidine	18 Years - 65 Years	AstraZeneca
Lorlatinib in Combination With Chemotherapy in Participants With Metastatic Anaplastic Lymphoma Kinase Positive (ALK+) Non-small Cell Lung Cancer (NSCLC) Who Progressed on Single-agent Lorlatinib	NCT05948462	Lung Cancer Non-small Cell ...	Lorlatinib Cisplatin or Ca... Pemetrexed	18 Years -	SCRI Development Innovations, LLC

Spots Global Cancer Trial Database for small molecule kinase inhibitor