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

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.

Inclusion criteria

• Patients with solid tumors (except pancreatic cancer) or non-Hodgkin lymphoma
• Metastatic disease or locally advanced inoperable tumor, not accessible to standard therapy.
• Male or female ≥ 18 years and <80 years.
• Tumor assessable by RECIST v1.1, Scher Cheson 2008 or 99.
• At least 28 days after completion of prior treatment (radiotherapy, systemic chemotherapy or major surgery).
• Patient who recovered from any prior toxicity ≤ grade 1.
• WHO 0-1 in the 7 days before inclusion.
• Neutrophils ≥ 1500/mm3, Platelets ≥ 100 000/mm3.
• Total bilirubin and serum creatinine within normal limits (≤ 1.5 ULN), creatinine clearance ≥ 40 ml / min.
• AST / ALT ≤ 1.5 ULN (≤ 5 ULN if liver metastasis).
• Normal thyroid function.
• Normal coagulation: TP ≥ 70%.
• Life expectancy upper than 3 months.
• HAD score <13.
• Negative pregnancy test for women likely to be pregnant within 7 days before inclusion.
• Effective contraception for the duration of treatment (for both sexes in childbearing or reproductive age): mechanic contraception method should always be used in combination with other contraceptive methods (eg, oral or other hormonal contraceptives). Because of long half-life of efavirenz, it is recommended to use adequate contraceptive measures for 12 weeks after stopping treatment with efavirenz.
• Informed consent signed and dated by the patient or his legal representative before the establishment of any specific procedure to the study.
• Clinical examination and laboratory tests made within 7 days before enrollment and start of treatment.
• Initial assessment and radiological CT / or MRI performed within 30 days before enrollment.
• Patients potentially compliant with treatment and follow-up study.
• Ability to swallow capsules or tablets.
• Patients insured by a social security system.

Exclusion criteria

• Patient with pancreatic cancer.
• Presence of active or symptomatic cerebral localization (known).
• History of another cancer except:

• cancer occurred more than five years and considered in complete remission
• in situ cervix carcinomas,
• cutaneous basal cell carcinomas.
• Current major depressive state (screening by HAD scale total score ≥ 13).
• Patients with history of depressive disorders, suicide attempts, addiction or other psychiatric disorders.
• Concomitant use of terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, alkaloids of ergot, voriconazole, mixing St. John's Wort.
• Patients treated with anti-vitamin K. Treatment with low molecular weight heparin are allowed.
• Known efavirenz hypersensitivity or to any of its excipients.
• Severe renal impairment.
• Severe hepatic impairment.
• Yellow fever vaccine (yellow fever).
• Pregnant or lactating.
• Presence of toxicity> 1 according to the criteria CTCAE V4.0, due to prior cancer therapy.
• Recurrent diarrhea which can interfere with drug absorption capacity.
• Patient included in another biomedical research on a drug within 30 days of inclusion.
• Patient who previously participated in this study.
• Patient, who for reasons psychological, psychiatric, social, family or geographical could not be treated or monitored regularly by the criteria of the study, patients deprived of liberty or under tutorship.