Intra-arterial Melphalan in Treating Younger Patients With Unilateral Retinoblastoma

• Sponsor: Children's Oncology Group (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02097134
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 14
• Locations: 12
• Arm: 1
• Anticipated Duration (Months): 131.4
• Patients Per Site: 1.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This pilot clinical trial studies whether unilateral group D retinoblastoma, or retinoblastoma affecting one eye that has spread to the inner jelly like part of the eye, can be treated with a new technique for delivering chemotherapy directly into the blood vessel that supplies the affected eye. This new technique is called intra-arterial injection. Giving melphalan via intra-arterial injection may make it less likely that children will need surgery to remove the eye and may reduce the amount of treatment side effects.

Condition or Disease	Intervention/Treatment	Phase
Unilateral Retinoblastoma	Drug: Melphalan	N/A

Detailed Description

PRIMARY OBJECTIVES:

1. To study the feasibility of delivering melphalan directly into the ophthalmic artery in children with newly diagnosed unilateral group D retinoblastoma, who would otherwise be considered for enucleation.

SECONDARY OBJECTIVES:

1. To estimate the ocular salvage rate after treatment with intra-arterial melphalan in children with newly diagnosed unilateral retinoblastoma with group D disease.

2. To evaluate the toxicities and adverse events associated with delivering multiple doses of intra-arterial chemotherapy.

3. To evaluate vision outcomes in children treated with intra-arterial chemotherapy.

4. To monitor the rate of the development of metastatic disease while on protocol therapy.

TERTIARY OBJECTIVES:

1. To evaluate the effects of intra-arterial therapy on the histopathology of eyes enucleated for progression.

OUTLINE:

Patients receive melphalan intra-arterially (IA) on day 1. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year, and then periodically for 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multi-institutional Feasibility Study of Intra-arterial Chemotherapy Given in the Ophthalmic Artery of Children With Retinoblastoma
• Actual Study Start Date: Apr 16, 2014
• Actual Primary Completion Date: Jun 30, 2017
• Anticipated Study Completion Date: Mar 30, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (melphalan) Patients receive melphalan IA on day 1. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.	Drug: Melphalan; Given IA; Other Names: Alanine Nitrogen Mustard CB-3025 L-PAM L-Phenylalanine Mustard L-sarcolysin L-Sarcolysin Phenylalanine mustard L-Sarcolysine Melphalanum Phenylalanine Mustard Phenylalanine nitrogen mustard Sarcoclorin Sarkolysin WR-19813

Outcome Measures

Primary Outcome Measures

1. Number of Patients Experiencing Feasibility Failure [Up to 4 months]

   Feasibility failure is defined as a) interventional radiologist is unable to access the ophthalmic artery for the 1st chemotherapy administration for any reason; b) patient develops central retinal artery occlusion after the 1st or 2nd course that does not reopen by the time the next injection is due; or c) the patient cannot receive all three treatments because of Common Terminology Criteria for Adverse Events (CTCAE) complications grade III or IV that are considered possibly, probably or likely related treatment.

Secondary Outcome Measures

1. Incidence of Grade 3 or Higher CTCAE Adverse Events Associated With Multiple Doses of IA Chemotherapy [Up to 30 days after completion of study treatment]

   The percentage of patients with at least 1 occurrence of grade 3 or higher CTCAE adverse experience will be provided. Ineligible patients or patients who do not receive any protocol therapy are excluded from reporting of adverse events.

2. Probability of Ocular Salvage [2 years]

   A patient will be considered an ocular-salvage success if enucleation because of disease progression or toxicity is not required during the 2 years following enrollment.

3. Rate of Metastases of Retinoblastoma [Up to 2 years]

   The percentage of patients who experience metastases of retinoblastoma will be estimated. Ineligible patients or patients who do not receive any protocol therapy are excluded from this analysis

4. Vision Acuity, Assessed According to the Amblyopia Treatment Study Visual Acuity Testing Protocol [1 year after therapy]

   Estimated by the average visual acuity amongst patients evaluated with a 95% confidence interval.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Months and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Newly diagnosed patients with unilateral group D retinoblastoma

• Magnetic resonance imaging (MRI) (or computed tomography [CT] if MRI is not available) of the brain must be performed within 14 days prior to study entry

• Diagnostic examination under anesthesia (EUA) must be performed within 14 days prior to study entry

• Rapid central review confirmation of group D disease based on RetCam images from diagnostic EUA must be obtained before starting treatment

• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2

• Patients must have a life expectancy of >= 8 weeks

• Patients must have adequate renal function, defined as:

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or

• A serum creatinine based on age/gender as follows:

• 1 month to < 6 months: 0.4 mg/dL

• 6 months to < 1 year: 0.5 mg/dL

• 1 to < 2 years: 0.6 mg/dL

• 2 to < 6 years: 0.8 mg/dL

• 6 to < 10 years: 1 mg/dL

• 10 to < 13 years: 1.2 mg/dL

• 13 to < 16 years: 1.5 mg/dL (male); 1.4 mg/dL (female)

• = 16 years: 1.7 mg/dL (male); 1.4 mg/dL (female)

• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age

• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x upper limit of normal (ULN) for age

Exclusion Criteria:

• Patients with bilateral disease

• Unilateral retinoblastoma with group A, B, C, or E eyes

• Prior chemotherapy or radiation therapy for this disease (laser and cryotherapy are allowed and are not considered exclusion criteria)

• Clinical or neuroimaging evidence of extraocular disease or orbital optic nerve involvement

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
2	UCSF Medical Center-Parnassus	San Francisco	California	United States	94143
3	UCSF Medical Center-Mission Bay	San Francisco	California	United States	94158
4	Yale University	New Haven	Connecticut	United States	06520
5	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida	United States	33136
6	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia	United States	30322
7	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
8	Duke University Medical Center	Durham	North Carolina	United States	27710
9	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
10	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
11	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas	United States	77030
12	M D Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• Children's Oncology Group
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Murali Chintagumpala, Children's Oncology Group

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 30, 2016

More Information

Publications

None provided.

• Responsible Party: Children's Oncology Group
• ClinicalTrials.gov Identifier: NCT02097134
• Other Study ID Numbers: ARET12P1; NCI-2014-00618; ARET12P1; ARET12P1; ARET12P1; U10CA180886; U10CA098543
• First Posted: Mar 26, 2014
• Last Update Posted: Jun 7, 2022
• Last Verified: Dec 1, 2021

• Additional relevant MeSH terms: Retinoblastoma; Melphalan; Mechlorethamine; Nitrogen Mustard Compounds

Study Results

Participant Flow

Arm/Group Title	Melphalan
Arm/Group Description	Patients receive melphalan intra-arterial (IA) on day 1. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Melphalan: Given IA
Period Title: Overall Study
STARTED	14
COMPLETED	5
NOT COMPLETED	9

Baseline Characteristics

Arm/Group Title	Melphalan
Arm/Group Description	Patients receive melphalan intra-arterial (IA) on day 1. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Melphalan: Given IA
Overall Participants	14
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	1.92 (0.93)
Sex: Female, Male (Count of Participants)
Female	5 35.7%
Male	9 64.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 35.7%
Not Hispanic or Latino	7 50%
Unknown or Not Reported	2 14.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 7.1%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 7.1%
White	8 57.1%
More than one race	0 0%
Unknown or Not Reported	4 28.6%
Region of Enrollment (participants) [Number]
United States	14 100%

Outcome Measures

1. Primary Outcome

Title	Number of Patients Experiencing Feasibility Failure
Description	Feasibility failure is defined as a) interventional radiologist is unable to access the ophthalmic artery for the 1st chemotherapy administration for any reason; b) patient develops central retinal artery occlusion after the 1st or 2nd course that does not reopen by the time the next injection is due; or c) the patient cannot receive all three treatments because of Common Terminology Criteria for Adverse Events (CTCAE) complications grade III or IV that are considered possibly, probably or likely related treatment.
Time Frame	Up to 4 months

Outcome Measure Data

Analysis Population Description

All Patients who are eligible and evaluable for the feasibility outcome are included in this outcome

Arm/Group Title	Melphalan
Arm/Group Description	Patients receive melphalan intra-arterial (IA) on day 1. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Melphalan: Given IA
Measure Participants	12
Number [participants]	4 28.6%

2. Secondary Outcome

Title	Incidence of Grade 3 or Higher CTCAE Adverse Events Associated With Multiple Doses of IA Chemotherapy
Description	The percentage of patients with at least 1 occurrence of grade 3 or higher CTCAE adverse experience will be provided. Ineligible patients or patients who do not receive any protocol therapy are excluded from reporting of adverse events.
Time Frame	Up to 30 days after completion of study treatment

Outcome Measure Data

Analysis Population Description

One patient who did not receive protocol therapy was excluded.

Arm/Group Title	Melphalan
Arm/Group Description	Patients will receive 1 intra-arterial injection (IA) of melphalan every 21- 30 days. Injections may be repeated every 21-30 days (up to a maximum of 3 cycles) assuming the patients meets the criteria to begin the next cycle.
Measure Participants	13
Number (95% Confidence Interval) [Percentage of patients]	38

3. Secondary Outcome

Title	Probability of Ocular Salvage
Description	A patient will be considered an ocular-salvage success if enucleation because of disease progression or toxicity is not required during the 2 years following enrollment.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

One patient who did not receive protocol therapy was excluded. Two patients who were lost to follow-up or follow-up was terminated electively prior to 2 years by patient or parent preference were excluded.

Arm/Group Title	Melphalan
Arm/Group Description	Patients will receive 1 intra-arterial injection (IA) of melphalan every 21- 30 days. Injections may be repeated every 21-30 days (up to a maximum of 3 cycles) assuming the patients meets the criteria to begin the next cycle.
Measure Participants	11
Number (95% Confidence Interval) [Percentage of patients]	36

4. Secondary Outcome

Title	Rate of Metastases of Retinoblastoma
Description	The percentage of patients who experience metastases of retinoblastoma will be estimated. Ineligible patients or patients who do not receive any protocol therapy are excluded from this analysis
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

One patient who did not receive protocol therapy was excluded.

Arm/Group Title	Melphalan
Arm/Group Description	Patients will receive 1 intra-arterial injection (IA) of melphalan every 21- 30 days. Injections may be repeated every 21-30 days (up to a maximum of 3 cycles) assuming the patients meets the criteria to begin the next cycle.
Measure Participants	13
Number [Percentage of Patients]	0

5. Secondary Outcome

Title	Vision Acuity, Assessed According to the Amblyopia Treatment Study Visual Acuity Testing Protocol
Description	Estimated by the average visual acuity amongst patients evaluated with a 95% confidence interval.
Time Frame	1 year after therapy

Outcome Measure Data

Analysis Population Description

The study was terminated at stage I since the therapy was considered not feasible to deliver. No patients had this data available. Patients either had affected eye enucleated, or did not complete protocol therapy.

Arm/Group Title	Melphalan
Arm/Group Description	Patients will receive 1 intra-arterial injection (IA) of melphalan every 21- 30 days. Injections may be repeated every 21-30 days (up to a maximum of 3 cycles) assuming the patients meets the criteria to begin the next cycle.
Measure Participants	0

Adverse Events

Time Frame	Up to 4 months
Adverse Event Reporting Description	The Other Adverse Events field contains Common Terminology Criteria for Adverse Events (CTCAEs) reported on protocol therapy, excluding those that were reported as Serious Adverse Events. The Serious Adverse Events field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs).
Arm/Group Title	Melphalan
Arm/Group Description	Patients receive melphalan intra-arterial (IA) on day 1. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Melphalan: Given IA
All Cause Mortality
	Melphalan
	Affected / at Risk (%)	# Events
Total	0/14 (0%)
Serious Adverse Events
	Melphalan
	Affected / at Risk (%)	# Events
Total	2/14 (14.3%)
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/14 (7.1%)
Vascular disorders
Hypotension	1/14 (7.1%)
Other (Not Including Serious) Adverse Events
	Melphalan
	Affected / at Risk (%)	# Events
Total	3/14 (21.4%)
Gastrointestinal disorders
Gastrointestinal disorders - Other, specify	1/14 (7.1%)
Immune system disorders
Anaphylaxis	1/14 (7.1%)
Investigations
Neutrophil count decreased	2/14 (14.3%)
Platelet count decreased	1/14 (7.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT 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.