QUILT-2.008: Study of ALT-801 With Cisplatin in Patients With Metastatic Melanoma

Sponsor

Altor BioScience (Industry)

Overall Status

Completed

CT.gov ID

NCT01029873

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Locations

Arm

Duration (Months)

3.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a Phase Ib/II, open-label, multi-center, competitive enrollment and dose-escalation study of ALT-801 combined with cisplatin. The purpose of this study is to evaluate the safety, determine the Maximum-Tolerated Dose (MTD), and characterize the pharmacokinetic profile of ALT-801 given with cisplatin in patients who are chemotherapy naïve and have metastatic melanoma that is considered surgically incurable. The anti-tumor responses of ALT-801 with cisplatin will also be assessed in this trial.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Melanoma	Drug: Cisplatin Biological: ALT-801	Phase 1/Phase 2

Detailed Description

Most current cancer treatment strategies involve the use of chemotherapeutic or biological drugs that exhibit variable efficacy and considerable toxicity. The limitations are often the result of the adverse side effects of the therapeutic drug on normal tissues. One approach to control these effects is to target the therapy to the tumor site. Of the identified tumor antigens, the human p53 tumor suppressor protein is overexpressed in a wide range of human malignancies. p53 is an intracellular tumor suppressor protein that acts to arrest the proliferation of cells. When mutated, it loses its ability to suppress abnormal proliferation and exhibits a longer half-life than the wild-type protein, allowing for its accumulation in tumors. In addition, p53 overexpression correlates with tumor transformation and aggression and is associated with lower overall survival rates and resistance to chemotherapeutic intervention in cancer patients. Therefore, p53 appears to be a marker for a considerable number of human malignancies and represents a good target for immunotherapeutics. However, p53 cannot be used as a target for antibodies because it is not displayed independently on the cell surface. Instead, the p53 protein is processed intracellularly into peptide fragments that are then displayed on the cell surface in the context of MHC. These peptide/MHC complexes are recognized by T-cells via their T-cell receptors (TCRs). Recently it has been confirmed that a p53 peptide fragment is significantly elevated in a wide range of human tumor tissues, particularly in melanoma, renal, lung, breast, colorectal, and osteosarcoma cancers. As a result, the feasibility of using soluble TCRs to target therapies against tumor cells that overexpress p53 is being investigated.

Interleukin-2 (IL-2) is a well-characterized growth factor for immune effector cells which play critical roles in tumor control and rejection. As a result, recombinant human IL-2 (e.g., Proleukin®, Chiron Novartis) has been approved for treatment of metastatic melanoma and renal cell carcinoma. IL-2 treatment provides significant benefit to a subset of patients with some maintaining durable responses for over ten years post-treatment. However, the major drawbacks of IL-2 therapy are its limited half-life and severe systemic toxicity. Hence, the use of high dose IL-2 is limited to specialized programs with experienced personnel, and it is generally offered to patients who are responsive and have excellent organ function. The low dose IL-2 treatment, while less toxic and more convenient, produces lower response rates and appears to be less effective in treating metastatic tumors. Thus, there is a critical need for innovative strategies that enhance the effects of IL-2 or reduce its toxicity without compromising clinical benefit. Targeted approaches to concentrate therapeutic cytokines, such as IL-2, at the tumor sites that express p53 could provide considerable advantages over current treatment.

The study drug, ALT-801, is a biologic compound composed of interleukin-2 (IL-2) genetically fused to a humanized soluble T-cell receptor directed against the p53-derived peptides expressed on tumor cells. This study is to evaluate whether directing IL-2 activity using ALT-801 to the patient's tumor sites that overexpress p53 results in clinical benefits if the ALT-801 treatment is given with cisplatin.

Platinum-based analogues including cisplatin, alone or in combination with other chemotherapies, have been shown to be active in patients with metastatic melanoma. Additionally, it is known that cisplatin, an alkylating agent known to inhibit DNA synthesis of dividing cells, triggers increased intracellular level of p53. The synergistic effects of cisplatin and ALT-801 treatment may induce cisplatin-mediated increases in p53 peptide display on the tumors and subsequently enhance tumor targeting of ALT-801.

Study Design

Study Type:

Interventional

Actual Enrollment :

25 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase Ib/II Study of ALT-801 With Cisplatin in Patients With Metastatic Melanoma

Study Start Date :

Feb 1, 2010

Actual Primary Completion Date :

Nov 1, 2011

Actual Study Completion Date :

Sep 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ALT-801	Drug: Cisplatin Intravenous infusions; 2 treatment courses; 2 treatment cycles for each course; 70mg/m2 on day 1 of cycle 1 for each course Biological: ALT-801 Intravenous infusions; cycle 1: day 3 and 5; cycle 2: day 1, 3 and 5; nine day rest period between cycles; seven day recovery period between courses Stage 1: dose escalation (0.04 mg/kg, 0.06 mg/kg, 0.08 mg/kg) Stage 2: dose expansion (dose at MTD)

Arm

Intervention/Treatment

Experimental: ALT-801

Drug: Cisplatin

Intravenous infusions; 2 treatment courses; 2 treatment cycles for each course; 70mg/m2 on day 1 of cycle 1 for each course

Biological: ALT-801

Intravenous infusions; cycle 1: day 3 and 5; cycle 2: day 1, 3 and 5; nine day rest period between cycles; seven day recovery period between courses Stage 1: dose escalation (0.04 mg/kg, 0.06 mg/kg, 0.08 mg/kg) Stage 2: dose expansion (dose at MTD)

Outcome Measures

Primary Outcome Measures

To evaluate the safety of the ALT-801-Cisplatin regimen. [12 months]
To assess the objective response (OR) which includes CR and PR. [3 months]
To assess the clinical benefit (CB) of the ALT-801-Cisplatin regimen which includes CR, PR and SD. [3 months]
To determine the MTD of the ALT-801-Cisplatin regimen. [7 weeks]

Secondary Outcome Measures

To assess the six-month and one-year survival rates. [12 months]
To evaluate the immunogenicity and pharmacokinetic profile of ALT-801. [2 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

ENTRY CRITERIA:

DISEASE CHARACTERISTICS:

Locally advanced or metastatic melanoma
Measurable
Histologically or cytologically confirmed
Surgically incurable
HLA-A2 positive and tumors that present HLA-A2.1/p53aa264-272 complexes

PRIOR/CONCURRENT THERAPY:

If prior Proleukin treatment, must have had clinical benefit
No prior systemic cytotoxic chemotherapy for melanoma
No concurrent radiotherapy, chemotherapy, or other immunotherapy
More than 4 weeks since prior major radiotherapy
More than 8 weeks since prior CTLA-4 antagonist immunotherapy
Not receiving other investigational agents

PATIENT CHARACTERISTICS:

Life expectancy

3 months

Performance status

ECOG 0 or 1

Bone marrow reserve

Absolute neutrophil count (AGC/ANC) ≥ 1,500/uL
Platelets ≥100,000/uL
Hemoglobin ≥ 10g/dL

Renal function

Serum creatinine ≤ 1.5 mg/dL

Hepatic function

Total bilirubin ≤ 1.5 X ULN
AST ≤ 2.5 X ULN
Alkaline phosphatase ≤ 2.5 X ULN
PT INR ≤ 1.5 X ULN
aPTT ≤ 1.5 X ULN

Cardiovascular

May be safely tapered off anti-hypertensives if currently on anti-hypertensives
New York Heart Association classification I or II
No congestive heart failure <6 months
No unstable angina pectoris <6 months
No myocardial infarction <6 months
No history of ventricular arrhythmias
Normal cardiac stress test required if any of the following is present:
Age ≥ 50
History of abnormal EKG
Symptoms of cardiac ischemia or arrhythmia

Pulmonary

Normal pulmonary function test (FEV1 ≥ 70% of predicted value) if any of the following is present:
Prolonged history of cigarette smoking
Symptoms of respiratory dysfunction

Other

No known autoimmune disease
No known HIV positive
No psychiatric illness/social situations that would limit study compliance
No history or evidence of CNS disease
No active systemic infection requiring parental antibiotic therapy
No systemic steroid therapy required
No prior organ allograft or allogeneic transplantation
Not receiving chronic medication for asthma
Not pregnant or nursing
Fertile patients must use effective contraception

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Angeles Clinic and Research Institute	Los Angeles	California	United States	90025
2	MD Anderson Cancer Center Orlando	Orlando	Florida	United States	32806
3	Emory University	Atlanta	Georgia	United States	30322
4	Northwestern University	Chicago	Illinois	United States	60611
5	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242
6	Carolinas Medical Center-Brumenthal Cancer Center	Charlotte	North Carolina	United States	28204
7	St. Luke's Hospital and Health Network	Bethlehem	Pennsylvania	United States	18015
8	University of Washington, Seattle Cancer Care Center	Seattle	Washington	United States	98109