Background
Methods/design
Objectives
Primary objective
Secondary objectives
Trial design
Summary of trial design
-
Total duration of the trial: 36 months:
-
Enrollment period: 20 months
-
Treatment: maximum of 6 cycles (5 months) per patient
-
Follow-up every three months
-
Step 1: 7 patients will be enrolled; on the basis of a minimax two-stage Simon design, a 40% immune response will preclude further study, whereas a 70% response rate will indicate that further study is warranted. Using alfa and beta errors of 0.10, if an immune response is observed in at least 3 of the 7 patients enrolled during the first stage, the study will go on with:
-
Step 2: recruitment of a further 12 patients.
Primary and secondary endpoints/outcome measures
-
immunological efficacy, assessed by quantification of circulating immune effectors specific for a selected panel of tumor antigens. In particular, this panel will include tumor antigens known to be highly expressed in over 80% of patients with melanoma or RCC in and whose expression must be confirmed in tumor biopsies taken before and after at least 2 cycles.
-
assessment of the predictive value of pretreatment serum biomarkers in identifying patients who will probably benefit from high-dose IL-2 based therapy. In particular, pretreatment concentrations of VEGF, fibronectin and proinflammatory cytokines (IL-1beta, IL-6, IL-8, IL-10, IL-12, alphaTNF) will be evaluated by SearchLight multiplex array analysis. Expression of CAIX in pretreatment biopsies from RCC patients will be evaluated by immunohistochemistry. In melanoma patients, tumor tissue biopsied before the start of treatment will be evaluated for the presence of N-Ras mutations.
-
toxicity, response rate and overall survival.
Study population
Inclusion criteria
-
ECG and echocardiogram within normal institutional limits.Pulmonary function tests within normal institutional limits (only to be performed in patients with lung metastases or history of impaired lung function).
Exclusion criteria
Study treatment
Radiotherapy
High-dose IL-2
Concomitant medications
-
3 bolus/day of desametazone 4 mg;
-
Ondansetron 8 mg ×2/day;
-
Paracetamol 500 mg ×3/day;
-
Adequate i.v. hydration.
Dose delays/modifications
Study treatment modifications
System | Relative criteria | Absolute criteria |
---|---|---|
Cardiac
| - Sinus tachycardia (120–130 beats per minutes); | - Sinus tachycardia (>130 beats per minutes persists after correcting hypotension, fever and stopping dopamine); |
- Atrial fibrillation; | ||
- Supraventricular tachycardia; | ||
- Ventricular arrhythmia; | ||
- Elevated creatine kinase isoenzymes or troponin; | ||
- Electrocardiogram changes of ischemia; | ||
Dermatologic
| --- | - Moist desquamation; |
Gastrointestinal
| - Diarrhea, up to 6 episodes/day | - Diarrhea, > 6 episodes/day |
- Ileus/abdominal distension; | - Severe abdominal distention affecting breathing; | |
- Bilirubin >7 mg/dl; | - Severe abdominal pain, unrelenting; | |
Hemodynamic
| - Maximum neosynephrine 1–1.5 mcg/kg/min; | - Maximum neosynephrine 1.5-2 mcg/kg/min; |
- Maximum neosynephrine >0.5 mcg/kg/min; | - Maximum neosynephrine >0.8 mcg/kg/min; | |
Hemorrhagic
| - Guiac + sputum, emesis, stool; | - Frank blood sputum, emesis, stool; |
- Platelets 30,000-50,000/mm3; | - Platelets <30,000/mm3; | |
Infections
| --- | - Strong clinical suspicion or documented; |
Muscoloskeletal
| - Weight gain >15%; | |
- Extremity tightness; | - Extremity paresthesias; | |
Neurologic
| - Vivid dreams; | - Hallucination; |
- Emotional lability; | - Persistent crying; | |
- Mental status changes not reversible in 2 hours; | ||
- Inability to subtract 7 s or spell “world” backwards | ||
disorientation; | ||
Pulmonary
| - Resting shortness of breath; | - >4 L O2 nasal cannula for saturation >95% or 40% O2 mask for saturation >95%; |
- 3-4 L O2 nasal cannula for saturation >95%; | - Moist rates involving more than half of both lung fields; | |
- Moist rates involving more than half of both lung fields; | - Endotracheal intubation; | |
- Pleural effusion requiring tap or chest tube; | ||
Renal
| - Urine 80–160 ml/shift; | - Urine <80 ml/shift; |
- Urine 10–20 ml/h; | - Urine <10 ml/h; | |
- Creatinine 2.5-2.9 mg/dl. | - Creatinine >3 mg/dl. |
Observation category | Action |
---|---|
Any relative criteria
| - Initiate corrective measure +/− delayed IL-2; |
Three criteria
| - Initiate corrective measure +/− delayed IL-2, stop IL-2 if not easily reversible; |
Any absolute criteria
| - Initiate corrective measure +/− delayed IL-2, stop IL-2 if not easily reversible. |
Measurement of effect
Primary endpoint/translational endpoint
Immunological efficacy
Secondary endpoints
Predictive value of pretreatment serum biomarkers
Tumor assessment
Index lesions | Non-index lesions | New measurable lesions | New non -measurable lesions | % Change in tumor burden | Overall irRC response |
---|---|---|---|---|---|
CR | CR | No | No | −100% | irCR |
PR | Any | Any | Any | ≥ −50% | irPR |
PR | Any | Any | Any | < −50% to < +25% | irSD |
PR | Any | Any | Any | ≥ +25% | irPD |
SD | Any | Any | Any | < −50% to < +25% | irSD |
SD | Any | Any | Any | ≥ +25% | irPD |
PD | Any | Any | Any | ≥ +25% | irPD |
SD | Any | Any | Any | < −50% to < +25% | irSD |
SD | Any | Any | Any | ≥ +25% | irPD |
PD | Any | Any | Any | ≥ +25% | irPD |
-
measurable new lesions are incorporated into the tumor burden (e.g. added to the index lesions) and do not define progression unless the total measurable tumor burden increases by the required amount (25%).
-
New non-measurable lesions (including bone lesions) are not considered progression if the total measurable tumor burden is stable or shrinking.
-
Changes in non-measurable lesions contribute only in the definition of irCR.
-
Progression of disease should be confirmed at two consecutive timepoints.
Radiologic assessment of tumor lesions
Method and timing
Secondary clinical efficacy endpoints based on irRC
-
Immune-related major durable disease control rate (irMDDCR): the proportion of treated subjects showing a disease control of 24 weeks measured from week 12, or from the date of the first overall response of irCR or irPR, until the date of irPD or death (whichever occurs first). For a subject who undergoes tumor resection following disease control but prior to disease progression, duration of disease control will be censored at the date of the last evaluable tumor assessment on or prior to the date of resection. Any subject who is unevaluable for MDDC for various reasons, e.g. censoring, lost to follow up, not assessable or unknown tumor assessments, will be considered a non-responder.
-
Immune-related objective response rate (irORR): the proportion of treated subjects with an immune-related best overall response (irBOR) of confirmed irCR or confirmed irPR.
-
Immune-related time to response (irTTR): the time from first dosing date until the measurement criteria (using irRC) are first met for overall response of irPR or irCR (whichever status comes first, and provided it is subsequently confirmed).
-
Immune-related duration of response (irDOR): the time between the date on which the measurement criteria (using irRC) are first met for an irCR or irPR (whichever status comes first and provided it is subsequently confirmed) and the date of irPD or death (whichever comes first). For a subject who undergoes tumor resection following response but prior to disease progression, irDOR will be censored on the date of the last evaluable TA or prior to the date of resection.For subjects who are still alive and have no progressive disease, as assessed by the investigator using irRC, irDOR will be censored on the date of the last evaluable tumor assessment.
-
Immune-related progression-free survival (irPFS): the time between the first dosing date and the date of irPD, or date of death, whichever occurs first (i.e. subjects who die without reported irPD will be considered to have progressed on the date of death). For subjects with no reported post-baseline tumor assessment, irPFS will be censored on the day of first dosing. For a subject who undergoes tumor resection following disease control but prior to disease progression, irPFS will be censored on the date of the last evaluable tumor assessment or prior to the date of resection. For subjects who are still alive and have no irPD, irPFS will be censored on the date of the last evaluable tumor assessment.
-
Overall survival (OS): the time from randomization until the date of death. For those subjects who are still alive, OS will be censored at the recorded last date of subject contact, and for subjects with a missing recorded last date of contact, OS will be censored at the last date the subject was known to be alive.
-
Immune-related time to progression (irTTP): the time from randomization to the first date of documented irPD (or death). Subjects without progression will be censored at their last tumor assessment date. Subjects without progression but who receive additional follow-up anticancer therapy will be censored on the date of their last tumor assessment prior to receiving the new therapy. Subjects with progression following additional anticancer therapy will also be censored on the date of their last assessment prior to receiving the therapy.
-
Death on study: any death occurring between the date of randomisation and up to 30 days after the end of treatment must be reported to the Coordinating Center within 24 hours as a serious adverse event (SAE), regardless of the relation to study drug(s). Deaths occurring during the study follow-up period (i.e. more than 30 days after the last vaccine dose) need only to be reported as an SAE if it is thought that there is a possible correlation with the study treatment(s). All deaths must be reported on the Death Report section of the CRF regardless of cause.
Statistical considerations
Study design/endpoints
Sample size/accrual rate
-
Step 1: 7 patients enrolled. A 40% immune response will preclude further study, whereas a 70% response rate will indicate that further study is warranted. Using alfa and beta errors of 0.10, if an immune response is observed in at least 3 of the 7 patients enrolled during the first stage, the study will go on with:
-
Step 2: recruitment of 12 additional patients.