Adjuvants, Anesthesia

Central Nervous System Depressants

Psychotropic Drugs

All Drugs and Chemicals

Midazolam

Cytochrome P-450 CYP3A Inhibitors

Anesthetics

Hypnotics and Sedatives

Anti-Anxiety Agents

Anesthetics, Intravenous

Anesthetics, General

GABA Modulators

Neurotransmitter Agents

Midazolam will be administered on Cycle 1 Day 1 and Cycle 1 Day 8. Capivasertib will be administrated from Cycle 1 Day 2 as an intermittent schedule (4 days on/3 days off) until discontinuation. On Cycle 1 Day 12, Midazolam will be administrated with Capivasertib.

Capivasertib (tablet) will be given as an intermittent schedule (4 days on/3 days off) from Cycle 1 Day 2 until discontinuation. Capivasertib will be administrated in both Part A and Part B.

Capivasertib

Single doses of midazolam (syrup, 1 mg) will be given on cycle 1 Days 1, 8, and 12.

This is an open-label, fixed-sequence study to evaluate the effect of capivasertib on the pharmacokinetics (PK) of midazolam, a sensitive CYP3A substrate. The PK of midazolam will be assessed when administered alone and in combination with repeated doses of capivasertib.

This is 2 part study: Part A and Part B. Part A of the study consists of a screening period and 3 treatment periods (midazolam alone, capivasertib alone, and midazolam + capivasertib). During Part A, the PK profile of midazolam will be determined with and without capivasertib.All participants will receive capivasertib treatment (4 days on/3 days off); however, at the Investigator's discretion, ER positive breast cancer patients may also receive fulvestrant in addition to capivasertib and midazolam. Participants completing Part A without disease progression or unacceptable toxicity, who are considered likely to continue to benefit from further capivasertib treatment (with or without certain standard of care treatment) in the opinion of the Investigator will enter Part B. Part B of the study consists of an extended treatment period with capivasertib, with or without certain standard of care treatment, followed by a 30-day safety follow-up.

Part A of the study may be extended to allow the administration of midazolam on a rescheduled Cycle 1 Day 8(C1D8) and Cycle 1 Day 12(C1D12 ) visit.

A Study to Assess the Effect of Capivasertib on Midazolam in Patients With Advanced Solid Tumours

An Open-label, Fixed-sequence Study to Assess the Effect of Repeated Doses of Capivasertib on the Pharmacokinetics of Oral Midazolam (a CYP450 3A Probe) in Patients With Advanced Solid Tumours

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.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

Area under the plasma concentration-time curve from zero to infinity

Maximum observed plasma (peak) drug concentration

Area under plasma concentration-time curve from zero to the last quantifiable concentration

Half-life associated with terminal slope (λz) of a semilogarithmic concentration-time curve

Time to reach peak or maximum observed concentration

Observed lowest drug concentration reached before the next dose is administered

Area under plasma concentration-time curve in the dose interval

Apparent total body clearance of drug from plasma after extravascular administration

Assessment of safety and tolerability of capivasertib (with or without the use of standard of care)and in combination with midazolam.

AstraZeneca

Neoplasms

All Conditions

Digestive System Diseases

Gland and Hormone Related Diseases

Infections

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Immune System Diseases

Rare Diseases

Carcinoma

Pancreatic Neoplasms

Adenocarcinoma

Acquired Immunodeficiency Syndrome

HIV Infections

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Gastrointestinal Neoplasms

Digestive System Neoplasms

Endocrine Gland Neoplasms

Gastrointestinal Diseases

Pancreatic Diseases

Endocrine System Diseases

Pancreatic Cancer

Antineoplastic Agents

Anti-Infective Agents

Paclitaxel

Gemcitabine

Albumin-Bound Paclitaxel

Cobicistat

Antiviral Agents

Enzyme Inhibitors

Anti-Retroviral Agents

Anti-HIV Agents

Cytochrome P-450 Enzyme Inhibitors

Tubulin Modulators

Antimitotic Agents

Antimetabolites

CYP3A Inhibitor Cobicistat and the cytostatics Gemcitabine and nab-Paclitaxel

Cobicistat Oral Tablet

Gemcitabin

Nab paclitaxel

Nicolas Hohmann, PD Dr. med.

Nicolas Hohmann, PD. Dr. med

To explore the possibility to overcome CYP3A-mediated resistance to anticancer drugs in pancreatic cancer, we will investigate the pharmacokinetics, safety, tolerability, and efficacy of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in combination with gemcitabine and the CYP3A inhibitor cobicistat in a phase I proof-of-concept trial to determine the safety profile, the recommended dose of nab-paclitaxel in combination with gemcitabine and cobicistat, and to determine whether there is an early efficacy signal warranting a larger scale trial.

The present trial is an open-label trial consisting of a dose-escalation part and an expansion part. The dose escalation part is designed to determine the safety, tolerability, and pharmacokinetics of nab-paclitaxel in combination with gemcitabine and cobicistat and will guide the dosing in the expansion part of the trial.

The trial enrolls patients with unresectable locally advanced or metastatic pancreatic adenocarcinoma and adequate performance score (ECOG PS 0-2) who would usually receive gemcitabine and nab-paclitaxel according to standard of care.

Primary endpoint for the phase I trial is the safety of the combination. Overall survival (OS), disease control rate (DCR), overall response rate (ORR), duration of response (DoR) and progression free survival (PFS) are secondary efficacy endpoints. Further secondary endpoints are tolerability, pharmacokinetics, pharmacodynamics, and pharmacogenomics.

A Trial of Cobicistat and Gemcitabine and Nab-Paclitaxel in Patients With Advanced Stage or Metastatic Pancreatic Ductal Adenocarcinoma

IntenSify: An Open-label Phase I Trial of the CYP3A Inhibitor Cobicistat and the Cytostatics Gemcitabine and Nab-Paclitaxel in Patients With Advanced Stage or Metastatic Pancreatic Ductal Adenocarcinoma to Evaluate the Combination's Pharmacokinetics, Safety and Efficacy

occurrence of DLTs within treatment cycle 1

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study to Assess the Effect of Capivasertib on Midazolam in Patients With Advanced Solid Tumours	NCT04958226	Solid Tumour	Capivasertib Midazolam	18 Years - 130 Years	AstraZeneca
A Trial of Cobicistat and Gemcitabine and Nab-Paclitaxel in Patients With Advanced Stage or Metastatic Pancreatic Ductal Adenocarcinoma	NCT05494866	CYP3A Inhibitor Advanced Stage ... Pancreatic Canc... Pancreatic Aden... Pancreatic Neop...	Cobicistat Oral... Gemcitabin Nab paclitaxel	18 Years -	German Cancer Research Center
A Study to Assess the Effect of Capivasertib on Midazolam in Patients With Advanced Solid Tumours	NCT04958226	Solid Tumour	Capivasertib Midazolam	18 Years - 130 Years	AstraZeneca
A Trial of Cobicistat and Gemcitabine and Nab-Paclitaxel in Patients With Advanced Stage or Metastatic Pancreatic Ductal Adenocarcinoma	NCT05494866	CYP3A Inhibitor Advanced Stage ... Pancreatic Canc... Pancreatic Aden... Pancreatic Neop...	Cobicistat Oral... Gemcitabin Nab paclitaxel	18 Years -	German Cancer Research Center

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