Dose Escalation Study of Nelfinavir Plus MLN9708 in Patients With Advanced Solid Tumors or Lymphoma

A Phase I Dose Escalation Study of Nelfinavir Plus MLN9708 in Patients With Advanced Solid Tumors or Lymphoma

This is an open label, dose escalation, phase I study of the combination of MLN9708 plus Nelfinavir.

This is an open label, dose escalation, phase I study of the combination of MLN9708 MLN9708 plus Nelfinavir. It will use a 3+3 cohort design to determine the maximum tolerated dose of the combination, which will be defined as the highest dose cohort where < 1/6 patients develop a dose limiting toxicity. The maximum tolerated dose cohort will be expanded to have at least 6 patients with biopsiable tumors who undergo pretreatment and post treatment tumor biopsies for molecular pharmacodynamic markers.

Inclusion Criteria

• Advanced or metastatic, histologically/cytologically confirmed malignant solid tumor or any lymphoma, not expected to clinically benefit from standard therapy.
• Life expectancy greater than 3 months.
• Previous chemotherapy and/or radiotherapy must have been completed at least four weeks before enrollment(six weeks for prior treatment with mitomycin or nitrosoureas) and patients should have recovered from all toxicities of that therapy before treatment under this protocol.
• All patients must have recovered from any surgical procedure.
• Serum creatinine must be within the institutional limits of normal and an estimated creatinine clearance of ≥ 60 mL/min.

Calculated by: Weight (in kg) X (140 - age) / (72 X Serum Creatinine)

• In females, multiply by 0.85. Alternatively, creatinine clearance may be measured from a 24 hour urine collection.

• Total bilirubin <2 x ULN. SGOT/AST and ALT must be less than or equal to 2.5 times the upper limit of institutional normal.

• Hb > 9.0 g/dL and absolute neutrophil count ≥ 1,500/mm3, and platelet count ≥ 100,000/mm3. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrollment.

• Patients must be 18 years of age or older.

• Patients must have a Karnofsky Performance Status of >70%

• Female patients who:

  • Are postmenopausal for at least 1 year before the screening visit, OR
  • Are surgically sterile, OR
  • If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, AND
  • Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
  • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, sympto-thermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)

• Male patients who:

  • Even if surgically sterilized (i.e., status post-vasectomy), must agree to one of the following:
  • Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR
  • Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
  • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, sympto-thermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)

• Brain metastases must be treated and stable for at least 3 months before the start of the treatment

• Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

Exclusion Criteria

• Inability or unwillingness to swallow capsules.
• Patients with active hepatitis B or C.
• Patients with known HIV infection.
• Ongoing or active systemic infection.
• Evidence of current uncontrolled cardiovascular conditions including, but not limited to uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.
• Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
• Pregnant or lactating female patients.
• Patients with malabsorption syndromes, or who have undergone a resection or bypass of the distal stomach/ pylorus, or small bowel.
• Participation in other clinical trials, including those with other investigational agents not included in this trial, within 21 days of the start of this trial and throughout the duration of this trial.
• Use of strong CYP 3A4 or P-gp inhibitors and/or inducers.
• Use of strong CYP 1A2 inhibitors and/or inducers.
• See Table of prohibited drugs (Appendix G).
• Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment.
• Failure to have fully recovered (i.e., < Grade 1 toxicity) from the reversible effects of prior chemotherapy.
• Major surgery within 14 days before enrollment.
• Radiotherapy within four weeks before enrollment. If the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of the MLN9708.
• Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
• Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
• Patient has > Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical examination during the screening period.