In this randomized controlled phase III study we will evaluate whether TIL infusion preceded by non-myeloablative chemotherapy and followed by high dose bolus interleukin-2 can result in an improved progression free survival when randomly compared…
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Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Progression free survival (according to RECIST 1.1).
Secondary outcome
PFS at 6 months (according to RECIST 1.1) and PFS according to irRC. Overall
response rate (RECIST 1.1 and immune related response criteria (irRC)),
complete response rate, overall survival and safety.
Background summary
Prior preclinical and clinical studies have shown that tumors from patients
with advanced melanoma contain tumor-infiltrating lymphocytes (TIL) with
anti-tumor reactivity targeting a variety of melanoma-associated antigens.
Prior clinical trials have shown that these TIL can be expanded in vitro using
interleukin-2 with anti-CD3 antibody stimulation and can cause regression of
melanoma when adoptively transferred back to the patient.
Preclinical mouse models and clinical studies have shown that host
immunosuppression prior to the adoptive transfer of tumor-reactive lymphocytes
greatly enhances their anti-tumor effect.
Using a preparative non-myeloablative regimen of cyclophosphamide and
fludarabine, a single institution phase II study in 43 patients showed a 51%
objective response rate to TIL and interleukin-2, with complete and durable
partial responses in a patient population that was heavily pretreated.
Thus, in this trial we will investigate whether TIL treatment improves
progression free survival (PFS) in a randomized phase III study compared to the
current standard of care (ipilimumab). If PFS is indeed significantly improved,
application of this approach for patients with advanced melanoma should be
pursued.
Study objective
In this randomized controlled phase III study we will evaluate whether TIL
infusion preceded by non-myeloablative chemotherapy and followed by high dose
bolus interleukin-2 can result in an improved progression free survival when
randomly compared to ipilimumab in stage IIIc and IV melanoma patients. A
health technology assessment (HTA) will be performed to evaluate the impact of
the TIL treatment on patients and organizational processes and
cost-effectivity.
Study design
Patients with irresectable or metastatic (stage IIIc or IV) melanoma and a
resectable metastasis will be randomized between arm A, standard treatment
(ipilimumab) and arm B, TIL treatment.
• Arm A: standard ipilimumab (3 mg/kg x 1 day i.v., q 3 weeks, maximal 4 times).
• Arm B: non-myeloablative chemotherapy (cyclophosphamide 60 mg/kg/day x 2 days
i.v., fludarabine 25 mg/m2/day x 5 days i.v.) followed by intravenous adoptive
transfer of at least 5 x 109 TIL followed by high dose interleukin-2
(Proleukin) (600.000 IU/kg/dose every 8 hours for up to 15 doses).
Intervention
Eligible patients (n=168) will be randomized between arm A and B. Patients that
are randomized in arm A will receive standard therapy with ipilimumab , 3
mg/kg, q 3 weeks, maximal 4 times. Patients that are randomized for arm B will
receive TIL treatment as described above. The patients for whom no TIL can be
generated, will be taken off-study. They will be treated with ipilimumab
according to the standard treatment arm but will be included in the intension
to treat analysis.
Study burden and risks
The TIL treatment will involve surgery of a melanoma metastasis of 2-3 cm,
in-hospital non-myeloablative chemotherapy, infusion of TIL and intravenous
high dose bolus IL-2 treatment. Although this treatment and toxicity has been
demonstrated to be well manageable, common toxicities from non-myeloablative
chemotherapy (transient bone marrow suppression requiring G-CSF for
neutropenia, red cell and platelet support, increased chance of bacterial,
viral and fungal infections, requiring antibiotics) and high dose IL-2 (high
fever, rash, low blood pressure and decreased urinary output, edema requiring
saline infusion support) may or will occur. Due to the infusion of TIL,
patients may develop signs of melanoma associated autoimmune diseases such as
vitiligo and uveitis. The latter, which is the more serious side effect, has
been shown to respond promptly to topical corticosteroid treatment. One patient
experienced prolonged toxicity after TIL treatment consisting of heart and
kidney failure, anemia and thrombocytopenia, possibly due to cyclophosphamide
and/or autoimmune effects of TIL. However, the fact that these patients may
have a high chance of durable objective responses, which otherwise would not
occur, justifies for the burden and possible toxicities.
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
• Histologically confirmed unresectable AJCC stage IIIc or stage IV melanoma
• Patients must have metastatic melanoma with a resectable metastatic lesion(s)
of sufficient size (>= 2-3 cm in total) and must be willing to undergo such a
resection for experimental purposes.
• Patients should have received no previous systemic therapy for unresectable
or metastatic melanoma or one line of any kind of systemic treatment, except
for ipilimumab.
• Patients must be >= 18 years and <= 75 years of age and must have measurable
disease by CT or MRI per RECIST 1.1 criteria (in addition to the resected
lesion).
• Patients must have a clinical performance status of ECOG 0 or 1.
• Patients of both genders must be willing to practice a highly effective
method of birth control during treatment and for four months after receiving
the preparative regimen.
• Patients must be able to understand and sign the Informed Consent document.
Exclusion criteria
• Life expectancy of less than three months.
• Patients with metastatic ocular/ mucosal or other non-cutaneous melanoma.
• Adjuvant treatment with ipilimumab within 6 months prior to randomization.
• Requirement for immunosuppressive doses of systemic corticosteroids (>10
mg/day prednisone or equivalent) or other immunosuppressive drugs within the
last 3 weeks prior to randomization.
• Patients who have a more than two CNS metastases.
• Patients who have any CNS lesion that is symptomatic, greater than 1 cm in
diameter or show significant surrounding edema on MRI scan will not be eligible
until they have been treated and demonstrated no clinical or radiologic CNS
progression for at least 2 months.
• All patients* toxicities due to prior non-systemic treatment must have
recovered to a grade 1 or less. Patients may have undergone minor surgical
procedures or focal palliative radiotherapy (to non-target lesions) within the
past 4 weeks, as long as all toxicities have recovered to grade 1 or less.
• Women who are pregnant or breastfeeding, because of the potentially dangerous
effects of the preparative chemotherapy on the fetus or infant.
• Any active systemic infections, coagulation disorders or other active major
medical illnesses.
• Any autoimmune disease
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-005406-54-NL |
| ClinicalTrials.gov | NCT02278887 |
| CCMO | NL47475.000.14 |