Single Dose of Intravenous rhTNF-α and Liposomal Doxorubicin in Patients With Advanced Solid Tumors or Lymphomas

• Maximum Tolerated Dose (MTD) of a single dose of intravenous recombinant human tumor necrosis factor-α plus liposomal doxorubicin [ Time Frame: Up to 22 days ] [ Designated as safety issue: Yes ]
  MTD is the dose level below the one that produces 2 or more Dose-Limiting Toxicities
• Dose Limiting Toxicity (DLT) of a single dose of intravenous recombinant human tumor necrosis factor-α plus liposomal doxorubicin [ Time Frame: up to 22 days ] [ Designated as safety issue: Yes ]

  Toxicity Criteria will be those listed in NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

  Any grade 3 cytokine release syndrome/acute infusion reaction or allergic and toxicity Grade 3 and above will be considered a DLT except:

  • Grade 3 toxicities that recover to grade 1 or less within 48 hours after standard supportive treatment.
  • Grade 4 neutropenia that recovers within 14 days.
  • Grade 4 thrombocytopenia that recovers within 14 days.
  • Grade 4 anemia that recovers within 14 days.

• Overall tumor response using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
• Caelyx/doxorubicin plasma levels [ Time Frame: 0, 24, 48 and 192 hours post‐dose ] [ Designated as safety issue: No ]
  Caelyx/doxorubicin plasma levels will be measured at 0, 24, 48 and 192 hours post‐dose by fluorimetry (excitation at 470nm, emission 590 nm) after liposomes have been disrupted in 70% ethanol, 0.3 N HCl

Assess the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of recombinant human tumor necrosis factor-α (rhTNF-α) when given as a single dose intravenously and in combination with liposomal doxorubicin in human subjects

• Solid Tumors
• Lymphomas

• Drug: Recombinant human TNF-α
  Infusion will be done over 60 minutes, preferably via central venous catheter. Will immediately follow the infusion of Liposomal doxorubicin.
  Other Name: Beromun
• Drug: Liposomal doxorubicin
  Infusion over 60 minutes
  Other Name: Caelyx
• Drug: Caelyx
  Administration of Caelyx® will be done first, as infusion in 250 ml D5W, followed immediately by infusion of rhTNF-α.
  Other Name: liposomal doxorubicin
• Drug: Recombinant human TNF-α
  Recombinant human TNF-α (Beromun) will be diluted in 250 mL of normal saline with albumin (2 mg/mL) to prevent adherence of the protein to the delivery apparatus. Infusion will be done over 60 minutes, preferably via central venous catheter, including PICC lines.
  Other Name: Beromun

• Experimental: rhTNF-α 25 µg/m² + Caelyx 40 mg/m²
  Cohort 2: rhTNF-α 25 µg/m² + Caelyx 40 mg/m²
  Interventions:

  • Drug: Recombinant human TNF-α
  • Drug: Liposomal doxorubicin
  • Drug: Caelyx
  • Drug: Recombinant human TNF-α
• Experimental: rhTNF-α 50 µg/m² + Caelyx 40 mg/m²
  Cohort 3: rhTNF-α 50 µg/m² + Caelyx 40 mg/m²
  Interventions:

  • Drug: Recombinant human TNF-α
  • Drug: Liposomal doxorubicin
  • Drug: Caelyx
  • Drug: Recombinant human TNF-α
• Experimental: rhTNF-α 100 µg/m² + Caelyx 40 mg/m²
  Cohort 4: rhTNF-α 100 µg/m² + Caelyx 40 mg/m²
  Interventions:

  • Drug: Recombinant human TNF-α
  • Drug: Liposomal doxorubicin
  • Drug: Caelyx
  • Drug: Recombinant human TNF-α
• Experimental: rhTNF-α 150 µg/m² + Caelyx 40 mg/m²
  Cohort 5: rhTNF-α 150 µg/m² + Caelyx 40 mg/m²
  Interventions:

  • Drug: Recombinant human TNF-α
  • Drug: Liposomal doxorubicin
  • Drug: Caelyx
  • Drug: Recombinant human TNF-α
• Experimental: rhTNF-α 200 µg/m² + Caelyx 40 mg/m²
  Cohort 6: rhTNF-α 200 µg/m² + Caelyx 40 mg/m²
  Interventions:

  • Drug: Recombinant human TNF-α
  • Drug: Liposomal doxorubicin
  • Drug: Caelyx
  • Drug: Recombinant human TNF-α
• Experimental: rhTNF-α 250 µg/m² + Caelyx 40 mg/m²
  Cohort 7: rhTNF-α 250 µg/m² + Caelyx 40 mg/m²
  Interventions:

  • Drug: Recombinant human TNF-α
  • Drug: Caelyx
  • Drug: Recombinant human TNF-α
• Experimental: rhTNF-α 25 µg/m² + Caelyx 30 mg/m²
  Cohort 1 rhTNF-α 25 µg/m² + Caelyx 30 mg/m²
  Interventions:

  • Drug: Recombinant human TNF-α
  • Drug: Liposomal doxorubicin
  • Drug: Caelyx
  • Drug: Recombinant human TNF-α

Inclusion Criteria:

• Patient must have a diagnosed solid tumor malignancy or lymphoma indicated for Caelyx treatment.
• Patient is refractory to all lines of standard therapy including biologics, chemo or other therapies, or at least one line of therapy in those patients for whom no standard treatment exists.
• Patient has measurable disease (defined as at least one lesion whose longest diameter can be accurately measured as >1 cm).
• At least 2 weeks has elapsed since the completion of the last cycle of chemotherapy and/or major surgery and the patient is fully recovered from this previous therapy or surgery and any post-surgical complications.
• The patient has a normal cardiac ejection fraction on MUGA or Echocardiogram.
• ECOG performance status of 2 or less.
• Patient is at least 18 years of age.
• Patient is capable of giving informed consent.
• Patient of childbearing potential is using adequate birth control measures (e.g., abstinence, barrier method with spermicide; intrauterine device, implantable or injectable contraceptives or surgical sterilization) for the duration of the study and will continue to use such precautions for 12 months after receiving treatment.

Exclusion Criteria:

• Positive pregnancy test or known pregnancy.
• Participation in any other clinical trial
• Known hypersensitivity to the active substance or to any of the excipients (Albumin).
• Patients exposed to greater than 450 mg/m2 of doxorubicin or Caelyx.
• Patient has a creatinine > 1.5 x the upper limit of normal, chronic renal failure requiring hemodialysis or peritoneal dialysis.
• Platelet count equal to or less than 50,000/mm3, Hemoglobin less than 9.0 g/dL, or an ANC less than 1,000 /mm3.
• Patient has a Sa02 of less than 93% on room air.
• Patient with detectable ascites or portosystemic hypertension or cirrhosis.
• Patient with bilirubin > 2.0, AST or ALT above 2.5X the upper limit of normal, an alkaline phosphatase above 2.5X the upper limit of normal.
• Hypercalcaemia > 12 mg/dl (2.99 mmol/l).
• Patients with contraindications to the use of vasopressor substances.
• Patient has presence of a transplanted solid organ (with the exception of a corneal transplant > 3 months prior to screening) or bone marrow transplant.
• Patient has a history of a significant medical illness deemed by the principal investigator or sub-investigators as unsuitable for the trial, for example: Significant cardiovascular disease, e.g. congestive heart failure (New York Heart Association Class II, III or IV), severe angina pectoris, cardiac arrhythmias, myocardial infarction within a 3 month period prior to treatment, venous thrombosis, occlusive peripheral arterial disease, recent pulmonary embolism. Severe pulmonary dysfunction. A recent history of, or active peptic ulcer. Severe ascites. Known hypotension.