A Study of ALT-801 in Combination With Cisplatin and Gemcitabine in Muscle Invasive or Metastatic Urothelial Cancer

Ureter Cancer Clinical Trial

Official title:

A Phase Ib/II Trial of ALT-801 in Combination With Cisplatin and Gemcitabine in Muscle Invasive or Metastatic Urothelial Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01326871
• Other study ID #: CA-ALT-801-01-10
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: September 6, 2011
• Est. completion date: April 11, 2016

Study information

• Verified date: April 2024
• Source: Altor BioScience
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a Phase Ib/II, open-label, multi-center, competitive enrollment and dose-escalation study of ALT-801 in a biochemotherapy regimen either containing cisplatin and gemcitabine or containing gemcitabine alone in patients who have muscle invasive or metastatic urothelial cancer of bladder, renal pelvis, ureters and urethra. The purpose of this study is to evaluate the safety, determine the maximum tolerated dose (MTD) and the recommended dose (RD), and assess the anti-tumor response of ALT-801 in combination with cisplatin and gemcitabine or ALT-801 in combination with gemcitabine alone. The pharmacokinetic profile of ALT-801 in combination with cisplatin and gemcitabine will also be assessed. The study includes a dose escalation phase (Phase Ib) and a dose expansion phase (Phase II). Phase II has two treatment groups, Expansion Group 1 and Expansion Group 2. Expansion Group 2 is for platinum-refractory patients, consisting of two treatment arms based on the patient's renal function. Patients will enroll to Expansion Group 2 after stage 1 of the Group 1 expansion is complete.

Description:

Bladder cancer is the fourth most common malignancy in men and the ninth most common in women in the US, with an estimated 68,810 new cases and 14,070 deaths for the year 2008. Approximately 90% to 95% of newly diagnosed patients are with transitional cell carcinomas (TCC). Approximately 20% to 25% contain advanced (muscle invasive or metastatic) disease. Muscle invasive bladder cancer is life threatening. Clinical trials have demonstrated that TCC is a chemotherapy-sensitive malignancy. Most current cancer treatment strategies involve the use of chemotherapeutic or biological drugs that have a low therapeutic ratio. The limitations are a consequence of effects of the therapeutic drug on normal tissues. One approach to control systemic exposure effects is to target the drug itself into the site of the tumor. For example, antibodies have been developed for use as tumor targeting agents and have had success in the clinic. However, despite the promise of antibody-based immunotherapy, there are limitations with these class of reagents. Even so, immunotherapy remains a promising approach to treat cancer.

One strategy that has received attention is treatment with cytokines such as IL-2 to enhance anti-tumor immunity. IL-2 has stimulatory effects on a number of immune cell types including T and B cells, monocytes, macrophages, lymphokine-activated killer cells (LAK) and natural killer (NK) cells. Based on the ability of IL-2 to provide durable curative anti-tumor responses, systemic administration of IL-2 has been approved to treat patients with metastatic melanoma or renal carcinoma. Unfortunately, the considerable toxicity associated with this treatment makes it difficult to achieve an effective dose at the site of the tumor and limits the population that can be treated. Thus, there is critical need for innovative strategies that enhance the effects of IL-2, to reduce its toxicity without compromising the clinical benefit, and to treat other diagnoses.

The study drug, ALT-801, is a biologic compound of interleukin-2 (IL-2) genetically fused to a humanized soluble T-cell receptor directed against the p53-derived peptides expressed on tumor cells. The p53 protein is one of the most important factors that protects from developing cancer and is also one of the most frequently mutated genes in many cancers, which include muscle-invasive bladder cancer. For any given cancer type, p53 dysfunction generally correlates with poor prognosis versus other the same site-of-origin. In some tumors, p53 mutation and over-expression also is associated with resistance to chemotherapy. This study is to further evaluate whether directing IL-2 activity using ALT-801 to the patient's tumor sites that over-express p53 results in clinical benefits

Recruitment information / eligibility

• Status: Completed
• Enrollment: 68
• Est. completion date: April 11, 2016
• Est. primary completion date: April 11, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

ENTRY CRITERIA:

DISEASE CHARATERISTICS:

• Muscle invasive or metastatic urothelial cancer of bladder, ureters, renal pelvis, and urethra

• Histologically or cytologically confirmed with a clinical plan that would potentially include cisplatin* plus gemcitabine systemic therapy or with disease refractory to a first-line platinum-based therapy (as defined in the protocol).

• Does not apply to patients screened for Phase II expansion

• Surgically incurable

PRIOR/CONCURRENT THERAPY:

• No concurrent radiotherapy, other chemotherapy, or other immunotherapy

• Must have recovered from side effects of prior treatments

• If prior Proleukin® treatment, must have had a clinical benefit

• No use of other investigational agents within 30 days of start or concurrently

PATIENT CHARACTERISTICS:

Age

• = 18 years

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

• Glomerular Filtration Rate (GFR):

• = 50mL/min/1.73m^2 for cisplatin-containing regimen

• = 40mL/min/1.73m^2 for non-cisplatin-containing regimen

Hepatic Function

• Total bilirubin = 1.5 X ULN

• AST, ALT, ALP = 2.5 X ULN, or = 5.0 X ULN (if liver metastases exists)

• PT INR = 1.5 X ULN

Cardiovascular

• No congestive heart failure < 6 months

• No unstable angina pectoris < 6 months

• No myocardial infarction < 6 months

• No history of ventricular arrhythmias

• No NYHA Class > II CHF

• Normal cardiac stress test required for subjects who are = 50 years old, or have a history of EKG abnormalities, or have symptoms of cardiac ischemia or arrhythmia

• No uncontrolled hypertension

Pulmonary

• Not receiving chronic medication for asthma

• Normal clinical assessment of pulmonary function

Hematologic

• No evidence of bleeding diathesis or coagulopathy

Other

• Negative serum pregnancy test if female and of childbearing potential

• No women who are pregnant or nursing

• Subjects, both females and males, with reproductive potential must agree to use effective contraceptive measures for the duration of the study

• No known autoimmune disease other than corrected hypothyroidism

• No known prior organ allograft or allogeneic transplantation

• Not HIV positive

• No active systemic infection requiring parenteral antibiotic therapy

• No ongoing systemic steroid therapy required

• No history or evidence of CNS disease (Controlled brain metastases treated with radiation therapy or surgery where the disease has been clinically stable for a period of a least 3 months before screening is allowed)

• No psychiatric illness/social situation

• No other illness that in the opinion of the investigator would exclude the subject from participating in the study

• Must provide informed consent and HIPAA authorization and agree to comply with all protocol-specified procedures and follow-up evaluations

Related Conditions & MeSH terms

• Carcinoma, Transitional Cell
• Malignant Tumor of Renal Pelvis
• Transitional Cell Carcinoma of Bladder
• Ureter Cancer
• Ureteral Neoplasms
• Urethra Cancer
• Urethral Neoplasms
• Urinary Bladder Neoplasms

Intervention

Drug:
• Cisplatin
Intravenous infusion; 3 initial treatment courses and an additional 3 maintenance courses for responders (maintenance revised for Phase II): on day 1 of each course (if given)
• Gemcitabine
Intravenous infusion; 3 initial treatment courses and an additional 3 maintenance courses for responders (maintenance revised for Phase II); on day 1 and 8 of each course

Biological:
• ALT-801
Intravenous infusion; 3 initial treatment courses and an additional 3 maintenance courses for responders (maintenance revised for Phase II): on day 3, 5, 8, and 12 of each course

Locations

Country	Name	City	State
United States	Emory University	Atlanta	Georgia
United States	Levine Cancer Institute	Charlotte	North Carolina
United States	Robert Lurie Comprehensive Cancer Center of Northwestern University	Chicago	Illinois
United States	Karmanos Cancer Center	Detroit	Michigan
United States	St. Luke's Hospital and Health Network	Easton	Pennsylvania
United States	University of Kansas Cancer Center	Fairway	Kansas
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	University of Minnesota	Minneapolis	Minnesota
United States	University of Oklahoma Health Science Center	Oklahoma City	Oklahoma
United States	UF Health Center at Orlando Health	Orlando	Florida
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	UPMC Cancer Center	Pittsburgh	Pennsylvania
United States	Washington University	Saint Louis	Missouri
United States	Martin Health System	Stuart	Florida
United States	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida
United States	The University of Arizona Cancer Center	Tucson	Arizona

Sponsors (2)

Lead Sponsor	Collaborator
Altor BioScience	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum Tolerated Dose (MTD) and/or the Recommended Dose (RD) for Dose Expansion of ALT-801 in Combination With Cisplatin and Gemcitabine or ALT-801 in Combination With Gemcitabine Alone		8 weeks
Primary	Safety Profile	Number of AEs that occur or worsen after the first dose of study treatment	8 weeks
Primary	Objective Response Rate in Treated Patients.	Number of participants with an objective response, which includes, a complete response,a partial response or a stable disease	12 weeks