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Cola

Dose escalation (0.015 mg/kg, 0.04 mg/kg, 0.08 mg/kg, 0.12 mg/kg, 0.14 mg/kg, 0.16 mg/kg), intravenous infusions, two treatment cycle, each cycle with 4 daily on-dose infusion, 10 days rest between cycles.

ALT-801

This is a Phase 1, open-labeled, non-randomized, multi-center, competitive enrollment and dose-escalation study of ALT-801, the study drug. The purpose of this study is to evaluate the safety, determine the maximum-tolerated dose (MTD) and characterize the pharmacokinetic profile of ALT-801 in previously treated patients with progressive metastatic malignancies. ALT-801, a recombinant fusion protein with a interleukin-2 (IL-2) component, has a targeting mechanism that recognizes tumor cells with a specific tumor marker.

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 major histocompatibility complex (MHC). These peptide/MHC complexes are recognized by T-cells via their T-cell receptors (TCRs). Recently it has been confirmed that the peptide fragment is significantly elevated in a wide range of human tumor tissues, particularly in melanoma, renal, lung, breast, colorectal, bladder, ovary, stomach, esophagus, lymphoma, liver, leukemia, and head \& neck cancer. Targeted approaches to concentrate therapeutic cytokines at the tumor sites that express p53 could provide considerable advantages over current treatment.

Interleukin-2 (IL-2) is a well-characterized growth factor for immune effector cells which play critical roles in tumor control and rejection. A recombinant human IL-2 has been approved for treating metastatic melanoma and renal cell carcinoma. However, the major drawback of IL-2 therapy is its severe systemic toxicity. As a result, 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. Thus, there is a critical need for innovative strategies that enhance the effects of IL-2 or reduce its toxicity without compromising clinical benefits.

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 antigen. 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.

The study drug will be administered by bolus intravenous infusion in an in-patient hospital setting under the supervision of a qualified physician experienced in the use of anti-cancer agents including high dose IL-2. An intensive care facility and specialists skilled in cardiopulmonary or intensive care medicine must be available. There are two treatment cycles. For each treatment cycle, patients will be admitted to the hospital, remain in the hospital during the study drug infusion period, and be discharged from the hospital the day after the last infusion at the Principal Investigator's discretion. There is a 10-day resting period between the treatment cycles. Tumor assessments will be done at weeks 7 and 11 after starting the study drug.

Safety and Efficacy Study of ALT-801 to Treat Progressive Metastatic Malignancies

Phase I Study of ALT-801 in Patients With Progressive Metastatic Malignancies

Number of serious adverse events per cohort

Number of dose limiting toxicities (DLTs). A DLT is a toxicity that results in patient withdrawal from the study as defined in the protocol.

Number of subjects with a complete response (CR), partial response (PR) or stable disease (SD). CR is defined as disappearance of all tumor lesions selected for measurement. PR is defined as at least 30% decrease in the sum of all tumor lesions selected for measurement. Stable disease is defined as neither sufficient tumor shrinkage to qualify for PR nor sufficient tumor increase to qualify for progressive disease (PD) which is defined as at least 20% increase the sum of the all tumor lesions selected for measurement.

Number of tumor-responsive (interferon-gamma positive (IFNg+)) immune cells in blood post dosing

Altor BioScience

ALT-801 0.015 mg/kg/Dose

ALT-801 0.040 mg/kg/Dose

ALT-801 0.080 mg/kg/Dose

Total

Age, Categorical

Age Continuous

Sex: Female, Male

Race (NIH/OMB)

Hing C. Wong, Chief Clinical Officer

The Safety and Toxicity of ALT-801 in Patients With Progressive Metastatic Malignancies

The Maximum-tolerated Dose (MTD) of ALT-801

Clinical Antitumor Response to ALT-801

ALT-801 Induced Cell-mediated Immune Responses

Immunogenicity of ALT-801

ALT-801 0.040 mg/kg/ Dose

Overall Study

Symptoms and General Pathology

Sarcoma

Recurrence

Sarcoma, Ewing

Rhabdomyosarcoma

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Myosarcoma

Osteosarcoma

Neoplasms, Bone Tissue

Neoplasms, Connective Tissue

Soft Tissue Sarcoma

Ewing Sarcoma

Vaccines

EF-1 Peptide

EF-2 Peptide

PXFK Peptide

E7 Peptide

IL-2

IL-4

GM-CSF

CD40 Ligand

Crystal L Mackall, M.D.

Arm A:

Peripheral blood apheresis by harvesting chemotherapy-naive T cells and populations enriched for professional APCs.

T cells and APCs are separated from the apheresis product using countercurrent centrifugal elutriation and a monocyte rich fraction is collected.

Autologous T cell transplantation during immunotherapy.

Arm B:

Cell harvesting is performed as soon as possible.

Both Arm A and B:

Patients receive intravenous infusion of irradiated peptide-pulsed antigen presenting cell vaccination (APC) products as well as intramuscular injection of influenza vaccine on the same day.

Recombinant human IL-2 is administered within 4 hours of the peptide pulsed vaccine by continuous intravenous infusion for 4 days per week for 3 successive weeks.

Primary toxic effect of this therapy is expected to be related to the IL-2 therapy. Patients with Grade 2 neurologic or cardiac or any Grade 3 or 4 toxic effects will discontinued IL-2 therapy. If toxic effect is not resolved in 72-hours, the patient may remain on study but will not receive any further IL-2.

Nearly all patients with non-metastatic Ewing's sarcoma family of tumors (ESFT) and alveolar rhabdomyosarcoma (AR) have a dramatic initial response to multiagent chemotherapy. However, approximately 30 percent of patients develop recurrent disease for which conventional chemotherapy is ineffective and treatment options are limited. Immunotherapy may represent an effective approach for treatment of recurrent ESFT and AR. Experimental evidence has shown that immune mediated anti-tumor effects can occur in vivo when T cells recognize and respond to antigens present on tumor cells. In ESFT and AR, tumor-specific chromosomal translocations resulting in the production of novel fusion proteins have been identified in the great majority of tumors. Peptides derived from these fusion proteins have been shown to function as tumor antigens for cytolytic T cells in animal studies. This protocol will study the safety, feasibility and efficacy of tumor-specific peptide vaccination administered with interleukin-2 therapy with or without autologous T cell infusions in patients with recurrent ESFT and AR.

A Pilot Study of Tumor-Specific Peptide Vaccination and IL-2 With or Without Autologous T Cell Transplantation in Recurrent Pediatric Sarcomas

National Cancer Institute (NCI)

Wounds and Injuries

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Hematologic Diseases

Breast Diseases

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Agranulocytosis

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Micronutrients

Molgramostim

Sargramostim

Leucovorin

Fluorouracil

FLAC chemotherapy with GM-CSF

This is a prospective, randomized Phase III trial of FLAC chemotherapy with GM-CSF versus PIXY321 in advanced breast cancer. The primary endpoints of this study will be the duration of thrombocytopenia and the time to recovery of platelets to 50,000/microliters. Other clinical endpoints will include the depth and duration of leukopenia, neutropenia, and anemia, the platelet and RBC transfusion requirements, and the number of documented instances of sepsis and hospitalizations for fever and neutropenia.

Laboratory correlates will include the detailed evaluation of the effects on circulating hematopoietic progenitor cells by GM-CSF and PIXY321 and the potential effects these agents have on the bone marrow micro-environment.

After 5 cycles of FLAC with GM-CSF versus PIXY321, patients will be treated with 5 cycles of 96 hour infusional taxol. The goal of this part of the study will be to assess the toxicity and feasibility of administering infusional taxol following dose-intensive FLAC chemotherapy.

A Prospective, Randomized, Phase III Trial of FLAC (5-Fluorouracil, Leucovorin, Adriamycin, Cytoxan) Chemotherapy With GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor) Versus PIXY 321 in Advanced Breast Cancer

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Safety and Efficacy Study of ALT-801 to Treat Progressive Metastatic Malignancies	NCT00496860	Progressive Met...	ALT-801	18 Years -	Altor BioScience
A Pilot Study of Tumor-Specific Peptide Vaccination and IL-2 With or Without Autologous T Cell Transplantation in Recurrent Pediatric Sarcomas	NCT00001564	Ewing's Sarcoma Rhabdomyosarcom...	EF-1 Peptide EF-2 Peptide PXFK Peptide E7 Peptide IL-2 IL-4 GM-CSF CD40 Ligand	- 30 Years	National Institutes of Health Clinical Center (CC)
A Prospective, Randomized, Phase III Trial of FLAC (5-Fluorouracil, Leucovorin, Adriamycin, Cytoxan) Chemotherapy With GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor) Versus PIXY 321 in Advanced Breast Cancer	NCT00001338	Breast Neoplasm... Fever Hematologic Dis... Neutropenia Sepsis	FLAC chemothera...	-	National Institutes of Health Clinical Center (CC)
A Prospective, Randomized, Phase III Trial of FLAC (5-Fluorouracil, Leucovorin, Adriamycin, Cytoxan) Chemotherapy With GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor) Versus PIXY 321 in Advanced Breast Cancer	NCT00001338	Breast Neoplasm... Fever Hematologic Dis... Neutropenia Sepsis	FLAC chemothera...	-	National Institutes of Health Clinical Center (CC)
A Prospective, Randomized, Phase III Trial of FLAC (5-Fluorouracil, Leucovorin, Adriamycin, Cytoxan) Chemotherapy With GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor) Versus PIXY 321 in Advanced Breast Cancer	NCT00001338	Breast Neoplasm... Fever Hematologic Dis... Neutropenia Sepsis	FLAC chemothera...	-	National Institutes of Health Clinical Center (CC)

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