Phase II Study of Interleukin-21 (rIL-21) vs Dacarbazine (DTIC) in Patients With Metastatic or Recurrent Melanoma

• Sponsor: NCIC Clinical Trials Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT01152788
• Collaborator: (none)
• Enrollment: 64
• Locations: 19
• Arms: 2
• Actual Duration (Months): 55.6
• Patients Per Site: 3.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to find out what effects an experimental drug, called interleukin 21 or rIL-21, will have on malignant melanoma and whether these effects look promising compared to dacarbazine. In addition, this study will look at the side effects of rIL-21, and some special blood tests will be done to check the level of rIL-21 in the blood. This study will also look at previously removed melanoma tissue to determine which patients might benefit most from this treatment.

This research is being done because currently there is no effective treatment for this type of cancer.

Condition or Disease	Intervention/Treatment	Phase
Melanoma	Drug: rIL-21; Drug: Dacarbazine	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 64 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II Study of Interleukin-21 (rIL-21) Versus Dacarbazine (DTIC) in Patients With Metastatic or Recurrent Melanoma
• Actual Study Start Date: Jun 28, 2010
• Actual Primary Completion Date: Nov 25, 2014
• Actual Study Completion Date: Feb 13, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: rIL-21	Drug: rIL-21; 30 μg/kg IV Daily x 5, weeks 1, 3 and 5 every 8 weeks
Active Comparator: Dacarbazine	Drug: Dacarbazine; 1000 mg/m2 IV Day 1, every 3 weeks

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival [From randomization to progression or death, up to 22 months]

   Progression free survival is defined as the time from randomization to the time of the first documented progression event or death by any cause. A patient who stops treatment with study drug and goes on to receive alternative therapy prior to documentation of disease progression, will be censored at the date alternative therapy began. If a patient has not progressed or received alternative therapy, progression free survival (PFS) will be censored at the date of the last disease assessment.

Secondary Outcome Measures

1. Response Rate [From the start of study treatment until the end of treatment (before disease progression)]

   Tumour response is defined per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete Response (CR): Disappearance of target and non-target lesions and normalization of tumour markers. Pathological lymph nodes must have short axis measures < 10 mm (Note: continue to record the measurement even if < 10 mm and considered CR). Residual lesions (other than nodes < 10 mm) thought to be non-malignant should be further investigated (by cytology or PET scans) before CR can be accepted. Confirmation of complete response is not required in this randomized study. Partial Response (PR): At least a 30% decrease in the sum of measures (longest diameter for tumour lesions and short axis measure for nodes) of target lesions, taking as reference the baseline sum of diameters. Confirmation of partial response is not required in this randomized study. Overall Response (OR) = CR + PR.

2. Overall Survival [From randomization to death of any cause, up to 22 months]

   For patients who have died, overall survival is calculated in months from the day of randomization to date of death. Otherwise, survival is censored at the last day the patient is known alive.

3. Safety and Toxicity Profile (Participants With Grade 3 4 5 Adverse Event) [Over study period, up to 22 months]

   To determine the safety and toxicity profile of rIL-21 and dacarbazine in patients with chemotherapy and immunotherapy-naive metastatic or recurrent malignant melanoma. Adverse events were measured according to the Common Terminology Criteria version 4.0 for Adverse Events. Number of patients with worst adverse event of grade 3 4 or 5 were counted for both rIL-21 and Dacarbazine arms.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically documented cutaneous malignant melanoma which is recurrent or metastatic and is not curable by surgical or other means.

• Patients must have tumour tissue from their primary and/or metastatic tumour available to assess putative molecular markers of response (paraffin block or 12 unstained slides).

• Presence of clinically and/or radiologically documented disease. At least one site of disease must be unidimensionally measurable as follows:

Chest X-ray > 20 mm, CT scan (with slice thickness of < 5 mm) >10 mm (longest diameter), Physical exam (using calipers) > 10 mm, Lymph nodes by CT scan > 15 mm measured in short axis.

All radiology studies must be performed within 21 days prior to randomization (Exception:

Within 28 days if negative).

• Patients must have either maximum tumour lesion size of ≤ 50 mm OR if tumour lesion is

50 mm, LDH must be ≤ 2.5 x ULN.

• Patients must have a life expectancy of at least 12 weeks.

• Age > 18 years.

• ECOG performance status of 0-1.

• Previous Therapy:

Immunotherapy: Prior adjuvant immunotherapy for melanoma is permitted if completed ≥ 1 month prior to study entry. No immunotherapy for metastatic disease is permitted. rIL-21 or dacarbazine must be the first systemic therapy for metastatic disease.

Chemotherapy: Patients must not have received any prior chemotherapy (including regional therapy). rIL-21 or dacarbazine must be the first systemic therapy for metastatic disease (except for RAF and MEK-Inhibitors).

Surgery: Previous surgery is permissible. Patient must be > 4 weeks since any major surgery.

Radiation Therapy: Previous radiation therapy is permitted with exception of radiation therapy for brain metastases. Patients must be > 4 weeks since the last treatment with radiation. Exceptions may be made, however, for low dose, non-myelosuppressive radiotherapy. Patients must have recovered from the toxic effects of radiation.

• Laboratory Requirements: (must be done within 7 days prior to randomization) Hematology: Absolute granulocytes (AGC) ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L Chemistry: Serum creatinine ≤ 1.5 x UNL, Bilirubin ≤ UNL AST and ALT ≤ 2.5 x UNL, LDH ≤ 2.5 x UNL.

• Female patients of child-bearing potential must have a negative serum or urine pregnancy test within 7 days of enrollment.

• Sexually active patients must agree to use a medically accepted form of contraception while receiving study therapy.

• Patient consent must be obtained according to local Institutional and/or University Human Experimentation Committee requirements. It will be the responsibility of the local participating investigators to obtain the necessary local clearance, and to indicate in writing to the NCIC CTG Study Coordinator that such clearance has been obtained, before the trial can commence in that centre. Because of differing requirements, a standard consent form for the trial will not be provided but a sample form is given in Appendix VII. A copy of the initial REB approval and approved consent form must be sent to the central office. The patient must sign the consent form prior to randomization. Please note that the consent form for this study must contain a statement which gives permission for qualified representatives of the NCIC CTG, BMS, ZymoGenetics, the company collaborator, and regulatory authorities to review patient records (see section 16 for further details) and a statement which gives permission for NCIC CTG to access and study tissue for biomarker assessments.

• Patients must be accessible for treatment and follow-up. Patients randomized on this trial must be treated and followed at the participating centre. This implies there must be reasonable geographical limits (for example: 2 hour's driving distance) placed on patients being considered for this trial.

• In accordance with NCIC CTG policy, protocol treatment is to begin within 5 working days of patient randomization.

Exclusion Criteria:

• Patients with known HIV, Hepatitis B or Hepatitis C infection.

• History of other malignancies, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for > 5 years.

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, myocardial infarction, other interventional cardiac procedure within the past 12 months, autoimmune conditions requiring chronic immunosuppressive therapy, or psychiatric illness/social situations that would limit compliance with study requirements.

• Patients may not have received any other investigational agents within 28 days of study entry, and may not receive concurrent treatment with other anti-cancer therapy or investigational agents while on protocol therapy.

• Patients with known brain metastases or history of CNS metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. A head CT or MRI is required on all patients to rule out brain metastases.

• Pregnant or lactating women. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with rIL-21 or dacarbazine, breastfeeding should be discontinued if the mother is treated with protocol therapy.

• Prohibited Medications: Long Term (> 7 days) Systemic Corticosteroids (e.g. prednisone, dexamethasone, etc.) because these may counteract the stimulatory effects of rIL-21 on lymphocytes. (Note: Topical steroids are allowed).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Angeles Clinic and Research Institute	Los Angeles	California	United States	90025
2	Tom Baker Cancer Centre	Calgary	Alberta	Canada	T2N 4N2
3	BCCA - Fraser Valley Cancer Centre	Surrey	British Columbia	Canada	V3V 1Z2
4	BCCA - Vancouver Cancer Centre	Vancouver	British Columbia	Canada	V5Z 4E6
5	BCCA - Vancouver Island Cancer Centre	Victoria	British Columbia	Canada	V8R 6V5
6	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
7	Atlantic Health Sciences Corporation	Saint John	New Brunswick	Canada	E2L 4L2
8	QEII Health Sciences Center	Halifax	Nova Scotia	Canada	B3H 1V7
9	Juravinski Cancer Centre at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8V 5C2
10	London Regional Cancer Program	London	Ontario	Canada	N6A 4L6
11	Ottawa Health Research Institute - General Division	Ottawa	Ontario	Canada	K1H 8L6
12	Northeast Cancer Center Health Sciences	Sudbury	Ontario	Canada	P3E 5J1
13	Odette Cancer Centre	Toronto	Ontario	Canada	M4N 3M5
14	Univ. Health Network-Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9
15	Hopital Charles LeMoyne	Greenfield Park	Quebec	Canada	J4V 2H1
16	CHUM - Hopital Notre-Dame	Montreal	Quebec	Canada	H2L 4M1
17	McGill University - Dept. Oncology	Montreal	Quebec	Canada	H2W 1S6
18	Allan Blair Cancer Centre	Regina	Saskatchewan	Canada	S4T 7T1
19	Saskatoon Cancer Centre	Saskatoon	Saskatchewan	Canada	S7N 4H4

Sponsors and Collaborators

• NCIC Clinical Trials Group

Investigators

• Study Chair: Teresa Petrella, Odette Cancer Centre - Sunnybrook Health Sciences Centre, Toronto, ON
• Study Chair: Kerry Savage, BCCA - Vancouver Cancer Centre, Vancouver, BC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: NCIC Clinical Trials Group
• ClinicalTrials.gov Identifier: NCT01152788
• Other Study ID Numbers: I202
• First Posted: Jun 29, 2010
• Last Update Posted: Dec 29, 2020
• Last Verified: Mar 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Melanoma; Dacarbazine

Study Results

Participant Flow

Arm/Group Title	rIL-21	Dacarbazine
Arm/Group Description	rIL-21: 30 μg/kg IV Daily x 5, weeks 1, 3 and 5 every 8 weeks	Dacarbazine: 1000 mg/m2 IV Day 1, every 3 weeks
Period Title: Overall Study
STARTED	32	32
COMPLETED	32	28
NOT COMPLETED	0	4

Baseline Characteristics

Arm/Group Title	rIL-21	Dacarbazine	Total
Arm/Group Description	rIL-21: 30 μg/kg IV Daily x 5, weeks 1, 3 and 5 every 8 weeks	Dacarbazine: 1000 mg/m2 IV Day 1, every 3 weeks	Total of all reporting groups
Overall Participants	32	28	60
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60	65	62
Sex: Female, Male (Count of Participants)
Female	9 28.1%	6 21.4%	15 25%
Male	23 71.9%	22 78.6%	45 75%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival
Description	Progression free survival is defined as the time from randomization to the time of the first documented progression event or death by any cause. A patient who stops treatment with study drug and goes on to receive alternative therapy prior to documentation of disease progression, will be censored at the date alternative therapy began. If a patient has not progressed or received alternative therapy, progression free survival (PFS) will be censored at the date of the last disease assessment.
Time Frame	From randomization to progression or death, up to 22 months

Outcome Measure Data

Analysis Population Description

treated population

Arm/Group Title	rIL-21	Dacarbazine
Arm/Group Description	rIL-21: 30 μg/kg IV Daily x 5, weeks 1, 3 and 5 every 8 weeks	Dacarbazine: 1000 mg/m2 IV Day 1, every 3 weeks
Measure Participants	32	28
Median (95% Confidence Interval) [years]	1.87	2.04

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rIL-21, Dacarbazine
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.76
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.10
	Confidence Interval	(2-Sided) 95%; 0.6 to 2.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Response Rate
Description	Tumour response is defined per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete Response (CR): Disappearance of target and non-target lesions and normalization of tumour markers. Pathological lymph nodes must have short axis measures < 10 mm (Note: continue to record the measurement even if < 10 mm and considered CR). Residual lesions (other than nodes < 10 mm) thought to be non-malignant should be further investigated (by cytology or PET scans) before CR can be accepted. Confirmation of complete response is not required in this randomized study. Partial Response (PR): At least a 30% decrease in the sum of measures (longest diameter for tumour lesions and short axis measure for nodes) of target lesions, taking as reference the baseline sum of diameters. Confirmation of partial response is not required in this randomized study. Overall Response (OR) = CR + PR.
Time Frame	From the start of study treatment until the end of treatment (before disease progression)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	rIL-21	Dacarbazine
Arm/Group Description	rIL-21: 30 μg/kg IV Daily x 5, weeks 1, 3 and 5 every 8 weeks	Dacarbazine: 1000 mg/m2 IV Day 1, every 3 weeks
Measure Participants	30	28
Number (95% Confidence Interval) [percentage of participants]	13.3 41.6%	14.3 51.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rIL-21, Dacarbazine
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-1.0
	Confidence Interval	(2-Sided) 95%; -18.7 to 16.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Overall Survival
Description	For patients who have died, overall survival is calculated in months from the day of randomization to date of death. Otherwise, survival is censored at the last day the patient is known alive.
Time Frame	From randomization to death of any cause, up to 22 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	rIL-21	Dacarbazine
Arm/Group Description	rIL-21: 30 μg/kg IV Daily x 5, weeks 1, 3 and 5 every 8 weeks	Dacarbazine: 1000 mg/m2 IV Day 1, every 3 weeks
Measure Participants	32	28
Median (95% Confidence Interval) [months]	6.6	7.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rIL-21, Dacarbazine
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.55
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95%; 0.38 to 1.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Safety and Toxicity Profile (Participants With Grade 3 4 5 Adverse Event)
Description	To determine the safety and toxicity profile of rIL-21 and dacarbazine in patients with chemotherapy and immunotherapy-naive metastatic or recurrent malignant melanoma. Adverse events were measured according to the Common Terminology Criteria version 4.0 for Adverse Events. Number of patients with worst adverse event of grade 3 4 or 5 were counted for both rIL-21 and Dacarbazine arms.
Time Frame	Over study period, up to 22 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	rIL-21	Dacarbazine
Arm/Group Description	rIL-21: 30 μg/kg IV Daily x 5, weeks 1, 3 and 5 every 8 weeks	Dacarbazine: 1000 mg/m2 IV Day 1, every 3 weeks
Measure Participants	32	28
Number [participants]	17 53.1%	6 21.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rIL-21, Dacarbazine
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	Chi-squared
	Comments

Adverse Events

Time Frame	22 months
Adverse Event Reporting Description	All grade 3 4 5 Adverse Events (5% or higher) were reported. All Serious Adverse Events were reported.
Arm/Group Title	rIL-21		Dacarbazine
Arm/Group Description	rIL-21: 30 μg/kg IV Daily x 5, weeks 1, 3 and 5 every 8 weeks		Dacarbazine: 1000 mg/m2 IV Day 1, every 3 weeks
All Cause Mortality
	rIL-21		Dacarbazine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	rIL-21		Dacarbazine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/32 (31.3%)		1/28 (3.6%)
Cardiac disorders
Atrial fibrillation	0/32 (0%)		1/28 (3.6%)
Gastrointestinal disorders
Duodenal obstruction	1/32 (3.1%)		0/28 (0%)
General disorders
Infusion related reaction	1/32 (3.1%)		0/28 (0%)
Gait disturbance	1/32 (3.1%)		0/28 (0%)
Hepatobiliary disorders
Hepatic failure	2/32 (6.3%)		0/28 (0%)
Immune system disorders
Autoimmune disorder	1/32 (3.1%)		0/28 (0%)
Infections and infestations
Sepsis	1/32 (3.1%)		0/28 (0%)
Injury, poisoning and procedural complications
Fall	1/32 (3.1%)		0/28 (0%)
Investigations
Aspartate aminotransferase increased	1/32 (3.1%)		0/28 (0%)
Alanine aminotransferase increased	1/32 (3.1%)		0/28 (0%)
Nervous system disorders
Ataxia	1/32 (3.1%)		0/28 (0%)
Renal and urinary disorders
Acute Kidney injury	1/32 (3.1%)		0/28 (0%)
Skin and subcutaneous tissue disorders
Other skin and subcutaneous tissue disorders	1/32 (3.1%)		0/28 (0%)
Vascular disorders
Hypotension	1/32 (3.1%)		0/28 (0%)
Other (Not Including Serious) Adverse Events
	rIL-21		Dacarbazine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/32 (37.5%)		3/28 (10.7%)
General disorders
Fatigue	2/32 (6.3%)		3/28 (10.7%)
Chest wall pain	2/32 (6.3%)		0/28 (0%)
Hepatobiliary disorders
Hepatic failure	2/32 (6.3%)		0/28 (0%)
Metabolism and nutrition disorders
Anorexia	2/32 (6.3%)		0/28 (0%)
Skin and subcutaneous tissue disorders
Skin and tissue	2/32 (6.3%)		0/28 (0%)
Rash maculo-papular	2/32 (6.3%)		0/28 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.