Phase I Dose Escalation Trial of Efavirenz in Solid Tumours or Non-Hodgkin Lymphoma in Therapeutic Failure.
Condition: Solid Tumors; Non-Hodgkin's Lymphoma
MeSH terms: Lymphoma; Lymphoma, Non-Hodgkin
Intervention: Efavirenz 600mg; Efavirenz 1200 mg; Efavirenz 1800 mg; Efavirenz 2200 mg
Intervention description: Efavirenz 600 mg (oral daily intake); Efavirenz 1200mg (oral daily intake); Efavirenz 1800mg (oral daily intake); Efavirenz 2200mg (oral daily intake)
Intervention MeSH terms: Efavirenz
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 25.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Solid tumors (other than pancreas)

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%.
    

Eligibility criteria:

        Inclusion Criteria :

          1. Patients with solid tumors (except pancreatic cancer) or non-Hodgkin lymphoma

          2. Metastatic disease or locally advanced inoperable tumor, not accessible to standard
             therapy.

          3. Male or female ≥ 18 years and <80 years.

          4. Tumor assessable by RECIST v1.1, Scher Cheson 2008 or 99.

          5. At least 28 days after completion of prior treatment (radiotherapy, systemic
             chemotherapy or major surgery).

          6. Patient who recovered from any prior toxicity ≤ grade 1.

          7. WHO 0-1 in the 7 days before inclusion.

          8. Neutrophils ≥ 1500/mm3, Platelets ≥ 100 000/mm3.

          9. Total bilirubin and serum creatinine within normal limits (≤ 1.5 ULN), creatinine
             clearance ≥ 40 ml / min.

         10. AST / ALT ≤ 1.5 ULN (≤ 5 ULN if liver metastasis).

         11. Normal thyroid function.

         12. Normal coagulation: TP ≥ 70%.

         13. Life expectancy upper than 3 months.

         14. HAD score <13.

         15. Negative pregnancy test for women likely to be pregnant within 7 days before
             inclusion.

         16. 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.

         17. Informed consent signed and dated by the patient or his legal representative before
             the establishment of any specific procedure to the study.

         18. Clinical examination and laboratory tests made within 7 days before enrollment and
             start of treatment.

         19. Initial assessment and radiological CT / or MRI performed within 30 days before
             enrollment.

         20. Patients potentially compliant with treatment and follow-up study.

         21. Ability to swallow capsules or tablets.

         22. Patients insured by a social security system.

        Exclusion Criteria :

          1. Patient with pancreatic cancer.

          2. Presence of active or symptomatic cerebral localization (known).

          3. History of another cancer except:

               -  cancer occurred more than five years and considered in complete remission

               -  in situ cervix carcinomas,

               -  cutaneous basal cell carcinomas.

          4. Current major depressive state (screening by HAD scale total score ≥ 13).

          5. Patients with history of depressive disorders, suicide attempts, addiction or other
             psychiatric disorders.

          6. Concomitant use of terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide,
             bepridil, alkaloids of ergot, voriconazole, mixing St. John's Wort.

          7. Patients treated with anti-vitamin K. Treatment with low molecular weight heparin are
             allowed.

          8. Known efavirenz hypersensitivity or to any of its excipients.

          9. Severe renal impairment.

         10. Severe hepatic impairment.

         11. Yellow fever vaccine (yellow fever).

         12. Pregnant or lactating.

         13. Presence of toxicity> 1 according to the criteria CTCAE V4.0, due to prior cancer
             therapy.

         14. Recurrent diarrhea which can interfere with drug absorption capacity.

         15. Patient included in another biomedical research on a drug within 30 days of inclusion.

         16. Patient who previously participated in this study.

         17. 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.