Phase I Dose Escalation Trial of Efavirenz in Solid Tumours or Non-Hodgkin Lymphoma in Therapeutic Failure.

Phase 1

Completed

Conditions: Solid Tumors
Non-Hodgkin's Lymphoma

Interventions: Drug: Efavirenz 600mg
Drug: Efavirenz 1200 mg
Drug: Efavirenz 1800 mg
Drug: Efavirenz 2200 mg

Registration Number: NCT01878890

Lead Sponsor: Institut Bergonié

Brief Summary: Hypothesis: encouraging results of phase II study FAVE in the treatment of hormonal resistant prostate cancer lead us to continue clinical development of efavirenz. Furthermore, all available pre-clinical and clinical data lead us to conduct a Phase 1 study with efavirenz. Objective of this Phase I is to test doses above 600 mg / day in patients with cancer in order to determine the maximum tolerated dose to improve therapeutic effect.

This study is a single center Phase I trial, conduct with dose escalation scheme of efavirenz by continual reassessment method likehood approach (CRML) on solid tumours (except pancreatic cancer) and non-Hodgkin lymphoma (NHL).

Main objective is to determine the safety profile, and particularly the maximum tolerated dose of efavirenz for the treatment of patients with solid tumors (except pancreatic cancer) or NHL in therapeutic failure.

Secondary objectives are:

* Evaluate efavirenz pharmacokinetics at 2, 4 and 12 weeks;

* Evaluate objective response at 12 weeks;

* Evaluate progression free survival at 6 months;

* Assess biological progression-free survival at 6 months (prostate tumours only).

Primary Endpoint

Safety will be evaluated according to the toxicity scale NCI-CTCAE v4.0. Dose limiting toxicities will be collected during the first 28 days (+ / - 7 days) after first dose of Efavirenz and will be defined as follows:

* Any drug-related toxicity with grade ≥ 3 according to NCI-CTCAE v4.0 (except alopecia, nausea and vomiting, regardless of grade),

* Any drug-related toxicity, regardless of grade, who led a treatment delay\> 14 days,

* Score ≥ 19 HAD during treatment. Secondary Criteria

* Solid tumors: response and progression defined by RECIST v1.1 \[Eisenhauer EA et al. EJC 2009).

* Non-Hodgkin lymphomas: Response and progression defined according to Cheson criteria \[Cheson BD et al. JCO 1999\]

* Biological progression (particular case of prostate tumors): defined according to Scher \[Scher HI et al. JCO 2008\] Statistical Considerations This is a Phase I dose escalation strategy using the method CRML, described by O'Quigley and Shen \[O'Quigley et al. Biometrics 1996\] and commonly used in Phase I trials in oncology.

* Maximum number of eligible and evaluable subjects is 30.

* Six dose levels are initially defined: 600 mg, 1200 mg, 1800 mg, 2200 mg, 2600 mg, 3000 mg.

* The risk of dose limiting toxicities maximum allowed is 25%.

Detailed Description: This is a Phase I dose escalation strategy according to the method described by CRML O'Quigley and Shen \[O'Quigley et al. Biometrics 1996\] and commonly used in phase I trials in oncology.

Six levels of doses are initially defined: 600 mg, 1200 mg, 1800 mg, 2200 mg, 2600 mg, 3000 mg.

The maximum potential dose-limiting toxicities allowed is 25%.

Dose limiting toxicities will be defined as follows:

* Any drug-related toxicity with grade ≥ 3 according to NCI-CTCAE v4.0 (except alopecia, nausea and vomiting, regardless of grade),

* Any drug-related toxicity, regardless of grade, who led a treatment delay\> 14 days,

* Score ≥ 19 HAD during treatment.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 25

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Efavirenz: 600 mg	Efavirenz 600mg	Cohort 1 : Participants received 600 mg of Efavirenz (oral / once a day), until progression or toxicity.
Efavirenz: 1200 mg	Efavirenz 1200 mg	Cohort 2 : Participants received 1200 mg of Efavirenz (oral / once a day), until progression or toxicity.
Efavirenz: 1800 mg	Efavirenz 1800 mg	Cohort 3 : Participants received 1800 mg of Efavirenz (oral / once a day), until progression or toxicity.
Efavirenz: 2200 mg	Efavirenz 2200 mg	Cohort 4 : Participants received 2200 mg of Efavirenz (oral / once a day), until progression or toxicity.

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose (MTD) of Efavirenz	Up to 28 days for each dosing cohort	MTD was determined by testing increasing doses up to 3000 mg (oral daily intake). The dose escalation scheme is the continual reassessment method likehood approach (CRML) described by O'Quigley and Shen \[O'Quigley et al. Biometrics 1996\]. MTD reflects the highest dose of drug that did not cause a Dose-Limiting Toxicity (DLT) in \> 25% of participants. A DLT was any drug-related toxicity with grade ≥ 3 according to NCI-CTCAE v4.0 (except alopecia, nausea and vomiting, regardless of grade), any drug-related toxicity, regardless of grade, who led a treatment delay\> 14 days, a score ≥ 19 for the Hospital Anxiety And Depression Scale (HAD) during treatment.
Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)	Up to 28 days for each dosing cohort	A DLT was any drug-related toxicity with grade ≥ 3 according to NCI-CTCAE v4.0 (except alopecia, nausea and vomiting, regardless of grade), any drug-related toxicity, regardless of grade, who led a treatment delay\> 14 days, a score ≥ 19 for the Hospital Anxiety And Depression Scale (HAD) during treatment.

Secondary Outcome Measures

Name	Time	Method
12-week Objective Response Rate	up to 3 months after first adminitration of Efavirenz	Objective response is defined as complete or partial response (CR, PR) using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Objective reponse rate is calculated as the number of patients with objective reponse divided by the number of alive patients.
12-week Non-progression Rate	Evaluated up to 3 months after first administration of Efavirenz	Non progression is defined as complete or partial response (CR, PR) or stable disease (SD), using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Non-progression rate is calculated as the number of alive and progression free patients divided by the number of patients.