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A Correlative Study of Melanoma Tumor-Infiltrating Lymphocytes (TILs) and Response to Ipilimumab

18 Years
Not Enrolling
Previously Untreated and Histologically Confirmed Stage III (Unresectable) or Stage IV Melanoma

Thank you

Trial Information

A Correlative Study of Melanoma Tumor-Infiltrating Lymphocytes (TILs) and Response to Ipilimumab


- Screening

− Assessment of the subject's eligibility to participate as determined by the
inclusion/exclusion criteria.

- Biopsy schedule

- Subjects will be biopsied according to the schedule in Section 7.

- Induction

- The recommended induction dose of ipilimumab is 10 mg/kg administered
intravenously over a 90-minute period every 3 weeks for a total of four doses, as

- Laboratory evaluations should be performed and the results examined before
administration of each ipilimumab dose.

- As durable disease stabilization and/or objective tumor response can be seen after
early progression before Week 12, it is recommended that, in the absence of
dose-limiting toxicities (eg, serious immune-mediated adverse reactions), all four
doses of ipilimumab be administered over the initial 12 weeks even in the setting
of apparent clinical progression, providing the subject's performance status
remains stable.

- All subjects who enter the induction period, including those who may have
discontinued treatment for drug-related AEs and/or who have evidence of clinical
progression during the induction period, should obtain a 12-week tumor assessment.

- Based on clinical experience in the ongoing and completed melanoma studies, the
following recommendations apply for subject management in light of the Week 12 or
later tumor assessments:

- The appearance of new lesions in subjects with other stable or shrinking baseline tumor
burden may be experiencing clinical benefit and should continue in follow-up and/or
maintenance therapy before alternative anti-cancer agents are considered. These
subjects can be seen to have continued tumor shrinkage in follow-up scans.

- As long as overall tumor burden is stable or decreasing, subjects should remain in
follow-up and/or maintenance (see below), even in the presence of new lesions.

- Clinical progression warranting alternative anti-cancer treatment should be considered
only in subjects whose overall tumor burden appears to be substantially increased
and/or in subjects whose performance status is decreased.

- Patients are eligible for retreatment treatments with ipilimumab on this protocol

- Follow-up

− Subjects will be required to attend a follow-up visit within 90 days of the last
ipilimumab treatment.

- Re-treatment

Patients who received ipilimumab at any dose in a prior/parent study and have met each of
the following criteria:

- Had no unacceptable toxicity requiring ipilimumab discontinuation; OR

- Patients who permanently discontinued treatment due to select irAEs as follows:

1. Reversible autoimmune hepatitis

2. Medically manageable endocrinopathy

3. Reversible dermatological toxicity AND

- Have experienced documented disease progression after demonstrating expanded clinical

Expanded clinical benefit is defined as:

- Patients whose disease is responding (partial response, complete response); or

- Patients whose disease was stable more than or equal to 3 months.

- Patients who demonstrated mixed or delayed response.

The mixed or delayed response is defined as follows:

Patients with Mixed Response: defined as at least 50% reduction in the bidimensional size of
one or more non-cystic lesions, even in the presence of any new lesions.

Patients with Delayed Response: defined as objective response (PR or CR) following
progressive disease, occurring any time after Week 12 in the prior/parent protocol, in
patients who have not received therapy with a non ipilimumab anti-cancer agent (approved or
experimental) between the PD and objective response.

Patients with select irAEs related to ipilimumab that have completely resolved with
immunosuppressive therapy or are adequately controlled with hormone therapy, may be
considered for further re-treatment with ipilimumab under this study, at the time of disease
progression. The list of completely reversible or medically managed immune-related adverse
events (irAEs) eligible for consideration are:

- Reversible autoimmune hepatitis

- Medically managed endocrinopathy

- Reversible dermatological toxicity All other irAEs are not considered eligible for
re-treatment, including, but not limited to, greater or equal Grade 3 colitis or
diarrhea, or uveitis of any grade.

Inclusion Criteria:

1. Willing and able give written informed consent.

2. Previously untreated and histologically confirmed Stage III (unresectable) or Stage
IV melanoma. Adjuvant interferon is acceptable however.

3. Subjects with asymptomatic brain metastases are eligible. (Systemic steroids should
be avoided if possible, or the subject should be stable on the lowest clinically
effective dose of steroids as they may interfere with the activity of ipilimumab if
administered at the time of the first ipilimumab dose.)

4. Must be at least 28 days since treatment with surgery or radiation, or immunotherapy
(IFN-alpha), and recovered from any clinically significant toxicity experienced
during treatment. Palliative radiation therapy outside of the brain or therapeutic
radiation to the brain after the subject's condition is stabilized and steroid
decreased to the lowest fixed dose possible does not require the 28- day waiting

5. Easter Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

6. Life expectancy of more than 16 weeks.

7. Subjects must have the complete set of baseline (screening/baseline) radiographic
images, including but not limited to brain, chest, abdomen, pelvis, and bone scans.
The images can be accepted if obtained 6 weeks before initiation of ipilimumab.

8. Required values for initial laboratory tests: WBC > 2000/uL; ANC > 1000/uL; Platelets
> 100 x 103/uL; Hemoglobin > 9 g/dL (> 80 g/L; may be transfused); Creatinine < 2.0 x
ULN; AST/ALT < 2.5 x ULN for patients without liver metastasis, > 5 times for liver
metastases; Bilirubin > 2.0 x ULN, (except patients with Gilber's Syndrome, who must
have a total bilirubin less than 3.0 mg/dL); INR > 1.3

9. No active or chronic infection HIV, Hepatitis B, or Hepatitis C.

10. Men and women, greater or equal to 18 years of age.

Exclusion Criteria:

1. Sex and Reproductive Status: a) WOCBP who are unwilling or unable to use an
acceptable method to avoid pregnancy for the entire study and for up to 8 weeks after
the last dose of investigational product. b) WOCBP using a prohibited contraceptive
method. c) Women who are pregnant or breastfeeding. D) Women with a positive
pregnancy test on enrollment or before investigational product administration.

2. Target Disease Exceptions: a) Subjects on any other systemic therapy for cancer,
including any other experimental treatment. b) Prior treatment with an anti- CTLA-4
antibody if treatment failure was due to irAEs. If a subject was discontinued from
the prior anti-CTLA-4 treatment due to an AE or SAE, regardless of the type of event,
that discontinuation constitutes an exclusion criterion. If irAEs were serious enough
to require a subject's withdrawal from prior treatment, the subject should be
excluded from this study. c) Prior treatment with
chemotherapy/biochemotherapy/immunotherapy for systemic disease for melanoma.

3. Primary ocular and mucosal melanomas are not allowed.

4. Medical History and Concurrent Diseases: a) Autoimmune disease: subjects with a
documented history of inflammatory bowel disease, including ulcerative colitis and
Crohn's disease are excluded from this study as are subjects with a history of
symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis
[scleroderma], Systemic Lupus Erythematosus, autoimmune vasculitis [e.g., Wegener's
Granulomatosis]). Subjects with motor neuropathy considered of autoimmune origin
(e.g., Guillain-Barre Syndrome and Myasthenia Gravis) are excluded from this study.
b) Any subject who has a life-threatening condition that requires high-dose
immunosuppressant(s). c) Presence of known hepatitis B or hepatitis C infection,
regardless of control on antiviral therapy. d) Subjects with melanoma who have
another active, concurrent, malignant disease with the exception of subjects with
adequately treated basal or squamous cell skin cancer, superficial bladder cancer, or
carcinoma in situ of the cervix.

5. Other Exclusion Criteria: a) Prisoners or subjects who are involuntarily
incarcerated. b) Subjects who are compulsorily detained fro treatment of either a
psychiatric or physical (e.g., infectious disease) illness. c) Any underlying medical
or psychiatric condition that, in the opinion of the investigator, could make the
administration of ipilimumab hazardous or could obscure the interpretation of adverse
events. d) Any non-oncology vaccine therapy used for prevention of infectious
diseases for up to 4 weeks before or after any dose of ipilimumab, with the
exceptions of amantadine and flumadine.

6. Any acute or chronic treatment with warfarin or antiplatelet agent (aspirin is
allowed up tot a dose of 300 mg daily) including clopidogrel. Heparin, low molecular
weight heparin, any heparinoid are allowed after appropriate cessation (usually 24

7. Any known or suspected bleeding diathesis on the basis or personal or family history
(including diagnoses of von Willebrands disease or other familial factor deficiency).

8. The risk of the excision involves a significant risk of morbidity or mortality due to
its size, location or vascularity (at the discretion of the principal investigators).

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

TILs characteristics

Outcome Description:

Tumor-infiltrating lymphocytes (TILs)will be observed before and after 10mg/kg Ipilimumab is administered on patients with Stage III (unresectable) or Stage IV melanoma.

Outcome Time Frame:

2 years

Safety Issue:


Principal Investigator

Anthony Joshua, M.D

Investigator Role:

Principal Investigator

Investigator Affiliation:

UHN-Princess Margaet Hospital


Canada: Health Canada

Study ID:




Start Date:

October 2012

Completion Date:

October 2014

Related Keywords:

  • Previously Untreated and Histologically Confirmed Stage III (Unresectable) or Stage IV Melanoma
  • melanoma
  • stage IV
  • stage III
  • unresectable
  • Melanoma