A Phase I Trial of the Combination of AZD2014 and Weekly Paclitaxel.

NCT02193633 | Completed Phase 1

• 2 other identifiers: CCR36672012-003896-20
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 4

Brief Summary

This is a Phase I study to evaluate the safety and toxicity profile of AZD2014, a novel anticancer agent, in combination with paclitaxel. AZD2014 will be given orally, twice daily at a starting dose of 25 mg per day for 3 days on, 4 days off with a weekly infusion of 80 mg of paclitaxel for 6 weeks followed by a treatment break of one week, therefore each cycle will be 7 weeks long. Cohorts of three patients will be treated at this dose of AZD2014 and then at 50mg and 75 mg providing is it safe to do so. Once we have determined the maximum tolerated dose (MTD) using the 3 days on, 4 days off schedule of AZD2014, patients will be given AZD2014 2 days on, 5 days with their paclitaxel infusion. Patients will be enrolled in cohorts of three to evaluate three escalating doses of AZD2014 to determine the MTD for the 2 days on, 5 days off schedule. On completion of the dose escalation phase of the study patients with ovarian cancer and squamous cell lung cancer will be treated at the MTD established for each dosing schedule. A minimum of 10 ovarian cancer patients and 15 squamous cell lung patients will be enrolled to the 3 days on, 4 days off schedule. Whilst a minimum of 10 squamous cell cancer patients will be enrolled to the 2 days on, 5 days off schedule to further assess the tolerability of the combination of AZD2014 and paclitaxel.

Conditions

Advanced Cancer

Outcome Measures

Primary Outcomes (1)

• Establish the maximum tolerated dose and recommended Phase II dose of two intermittent dosing schedules of AZD2014: 3 days on, 4 days off and 2 days on, 5 days off in combination with weekly paclitaxel in patients with solid tumours.

  To determine the dose at which no more than one patient out of up to 6 patients at the same dose level experience a drug-related dose-limiting toxicity.

  First cycle of treamtent (7 weeks)

Secondary Outcomes (2)

• PK parameters for AZD2014 and paclitaxel derived from determining their plasma concentrations using validated assays.

  First cycle of treatment (7 weeks)

• PK parameters for AZD2014 and paclitaxel derived from determining their plasma concentrations using validated assays

  First cycle of treatment (7 weeks)

Other Outcomes (1)

• To document any possible anti-tumour activity

  Duration of the study

Study Arms (2)

AZD2014 3 on/4 off & weekly paclitaxel

EXPERIMENTAL

3 days on, 4 days off AZD2014 BD administered orally Days 1-3 each week in combination with paclitaxel administered via IV infusion on Day 1 each week, in 7-week cycles (6 weeks treatment followed by 1 week rest).

Drug: AZD2014 3 on/4 off & weekly paclitaxel

AZD2014 2 on/5 off & weekly paclitaxel

EXPERIMENTAL

AZD2014 BD administered orally Days 1-2 each week in combination with paclitaxel administered via IV infusion on Day 1 each week, in 7-week cycles (6 weeks treatment followed by 1 week rest).

Drug: AZD2014 2 on/5 off & weekly paclitaxel

Interventions

AZD2014 3 on/4 off & weekly paclitaxel DRUG

AZD2014 3 days on, 4 days off + weekly paclitaxel

Also known as: AZD2014, AZD2014 3 days on, 4 days off, Paclitaxel

AZD2014 3 on/4 off & weekly paclitaxel

AZD2014 2 on/5 off & weekly paclitaxel DRUG

AZD2014 2 days on, 5 Days off + weekly paclitaxel

Also known as: AZD2014, AZD2014 2 days of, 5 days off, Paclitaxel

AZD2014 2 on/5 off & weekly paclitaxel

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically or cytologically proven solid tumour.refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient, or where treatment with paclitaxel is an appropriate treatment option. Patients enrolled in the expansion phase must have recurrent ovarian, fallopian tube or primary peritoneal cancer only.
• Patients who have had conventional treatment and where paclitaxel is appropriate. In instances where paclitaxel is appropriate but the patients has not already received it the patient may be enrolled after discussion between the referring oncologist and Principal Investigator.
• Life expectancy of at least 12 weeks
• ECOG performance status of 0-1
• Females should be using adequate contraceptive measures, should not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential
• Male patients should be willing to use barrier contraception i.e., condoms
• Measurable or evaluable disease. Patients enrolled in the expansion phase should have measurable disease by RECIST v1.1 criteria
• Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week (Day -7 to Day 1) before the patient goes in the trial.
• Haemoglobin (Hb)≥ 9.0 g/dL
• Absolute neutrophil count ≥ 1.5 x 109/L
• Platelet count ≥ 100 x 109/L
• Serum bilirubin ≤ 1.5 x upper limit of normal (ULN)
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST)≤ 2.5 x (ULN) if no demonstrable liver metastases or ≤ 5 times ULN in the presence of liver metastases
• Alkaline phosphatase (ALP)\< 5 x ULN
• Creatinine Clearance ≥ 50 mL/min (uncorrected value)OR Serum creatinine ≤ 1.5 x ULN

You may not qualify if:

• Radiotherapy (except for palliative reasons), chemotherapy, endocrine therapy, or immunotherapy during the previous 3 weeks (4 weeks for investigational medicinal products and 6 weeks for nitrosoureas and Mitomycin-C) before treatment.
• N.B. Exceptions to this are patients receiving weekly taxol as standard of care who have not had a partial or complete response after 6 to 12 weekly doses. Those patients should discontinue their weekly taxol treatment and may be enrolled to the dose expansion phase without a wash out period.
• CTCAE Grade 1 or higher toxicities from previous systemic anticancer therapy prior to the first dose of study treatment (with the exception of alopecia)
• Known leptomeningeal involvement, brain metastases or spinal cord compression
• Known hypersensitivity (\>Grade 2) to taxanes, drugs containing Cremophor, AZD2014 or structurally/chemically similar drugs
• Unresolved bowel obstruction
• Current refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow formulated product or previous significant bowel resection that would preclude adequate absorption of AZD2014
• Patients with Diabetes Type I or uncontrolled Type II (HbA1c \>59 mmol/mol assessed locally) as judged by the investigator
• Major surgery within 4 weeks prior to entry to the study (excluding placement of vascular access), or minor surgery within 2 weeks of entry into the study and from which the patient has not yet recovered
• Treatment with warfarin. Patients on warfarin for DVT/PE can be converted to LMWH.
• Potent and moderate inhibitors and inducers of CYP3A4/5 if taken within the stated washout periods:
• Inhibitors (competitive): ketoconazole, itraconazole, indinavir, saquinovir, nelfinavir, atazanavir, amprenavir, fosamprenavir, troleandomycin, telithromycin, fluconazole, nefazodone, cimetidine, aprepitant, miconazole, fluvoxamine (1 week minimum wash-out period), amiodarone (27 week minimum wash-out period)
• Inhibitors (time dependent): erythromycin, clarithromycin, verapamil, ritonavir, diltiazem (2 week minimum wash-out period)
• Inducers: phenytoin, rifampicin, St. John's Wort, carbamazepine, primidone, griseofulvin, barbiturates, troglitazone, pioglitazone, oxcarbazepine, nevirapine, efavirenz, rifabutin (3 week minimum wash-out period) and phenobarbitone (5 week minimum washout period)
• Potent and moderate inhibitors and inducers of CYP2C8 if taken within the stated washout periods:

Sponsors & Collaborators

• Royal Marsden NHS Foundation Trust: lead
• Institute of Cancer Research, United Kingdom: collaborator
• AstraZeneca: collaborator

Study Sites (4)

Addenbrookes Hospital

Cambridge, Cambridgeshire, CB2 0QQ, United Kingdom

Location

Royal Marsden Hospital

Sutton, Surrey, SM2 5PT, United Kingdom

Location

Belfast City Hospital

Belfast, BT9 7AB, United Kingdom

Location

Guy's and St Thomas's NHS Foundation Trust

London, SE1 9RT, United Kingdom

Location

Related Publications (1)

• Basu B, Krebs MG, Sundar R, Wilson RH, Spicer J, Jones R, Brada M, Talbot DC, Steele N, Ingles Garces AH, Brugger W, Harrington EA, Evans J, Hall E, Tovey H, de Oliveira FM, Carreira S, Swales K, Ruddle R, Raynaud FI, Purchase B, Dawes JC, Parmar M, Turner AJ, Tunariu N, Banerjee S, de Bono JS, Banerji U. Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high-grade serous ovarian and squamous non-small-cell lung cancer. Ann Oncol. 2018 Sep 1;29(9):1918-1925. doi: 10.1093/annonc/mdy245.

  PMID: 30016392 BACKGROUND

MeSH Terms

Interventions

vistusertib; Paclitaxel

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Study Officials

• Udai Banerji, PhD

  The Institute of Cancer Research, Royal Marsden NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 10, 2013
• First Posted: July 17, 2014
• Study Start: April 26, 2013
• Primary Completion: November 15, 2017
• Study Completion: November 15, 2017
• Last Updated: September 26, 2024

Record last verified: 2020-02

Locations

GB (4)