RNActive®-Derived Therapeutic Vaccine

Study Overview
=================
Brief Summary
-----------------
This is a Phase I/IIa open, uncontrolled, prospective study, to be conducted in an out-patient setting. The present study is one of two clinical trials of the RNActive®-derived vaccine CV9103 being conducted concurrently in the US and Europe, which represent the first clinical trials conducted for this novel vaccine. The Phase I part of the study consists of a staggered inclusion of subjects in two cohorts of 3, to confirm the safety of the intended dose (320 µg RNA per antigen), with a lower dose to be considered in case of dose-limiting toxicity (DLT) being reported in greater than or equal to 2 out of 3-6 subjects; in this way, the recommended dose (RD) for the Phase IIa part of the study will be established. In the Phase IIa part of the study, additional subjects will be included at the RD, to confirm the safety and explore the activity of that dose.

Detailed Description
-----------------
Medical Need: At present, no curative therapy is available for subjects with advanced or metastatic prostate cancer. Approximately 1 of every 3 men present with advanced or metastatic disease; therefore, current standard therapies are ineffective and new therapeutic approaches are warranted. There is ample evidence that active immunotherapy against cancer is safe and capable of stimulating potentially therapeutic immune responses in the cancer patient. Moreover, several Phase II immunotherapy trials have suggested clinical benefit by reducing the tumor mass or prolonging time to progression in subjects with advanced prostate cancer. Potential Benefits: CV9103 is an mRNA-based vaccine for the treatment of human prostate cancer that is based on CureVac's RNActive® technology. CV9103 encodes for 4 prostate specific antigens. Because these antigens are present in prostate cancer cells, they are appropriate targets for intervention. These antigens have been shown to correlate frequently with the progression of prostate cancer, and are known to be immunogenic in humans, where they induce antigen specific T-cell or B cell expansion. As an RNA-based vaccine, CV9103 features several advantages over other approaches: it is highly specific, there is no restriction to the patient's MHC genotype, and it does not need to cross the nuclear membrane to be active. Finally, in the absence of reverse transcriptase, RNA can not be integrated into the genome. CV9103 will be administered in 5 doses.

Official Title
-----------------
Phase I/IIa Study of RNActive®-Derived Therapeutic Vaccine in Advanced or Metastatic Hormone Refractory Prostate Cancer

Conditions
-----------------
Hormone Refractory Prostate Cancer

Intervention / Treatment
-----------------
* Biological: CV9103


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects with documented history of hormone refractory prostate cancer as evidenced by three consecutive increases in serum PSA despite continued androgen ablative therapy. Serum testosterone levels must be less than 50 ng/dl Signed informed consent in accordance with Good Clinical Practice (GCP) and local regulatory requirements prior to trial participation Age greater than or equal to 18 yrs (Phase I and IIa) and less than or equal to 75 yrs (Phase IIa only) ECOG (Eastern Cooperative Oncology Group) Grade of 0 or 1 Adequate Hematologic Function with: WBC ≥ 3000 mm3 hemoglobin ≥ 10mg/dl platelets ≥ 100,000/mm3 Adequate Renal and Hepatic Function with: serum creatinine ≤ 1.5 x Upper Limit of Normal bilirubin < 2.0 mg/dl Adequate Coagulation Parameters with: Prothrombin INR < 1.5 Partial Thromboplastin Time < 1.5 x Institutional Upper Limit of Normal Subjects will be advised to use barrier contraception while enrolled in the study and for one month after the last immunization. Life Expectancy > 6 month Exclusion Criteria: Subjects who have received radiation therapy within 8 weeks of pretreatment evaluation. (There must be at least 12 weeks if prior therapy included 89-Strontium between any prior therapy and study entry.) Subjects who have received chemotherapy, radiation therapy or biologic regimens within 8 weeks of pretreatment evaluation. Subjects treated with any investigational agent within the past 30 days are excluded. Subjects who have received active immunotherapy, such as Antigen Loaded Dendritic Cells, are excluded (Phase I only). In Phase IIa, Subjects who have received an active immunotherapy based on any of the antigens used in this study either as DNA, RNA or a protein/peptide-based vaccines are excluded. Subjects who have received any other active immunotherapy, such as Antigen Loaded Dendritic Cells, within 6 months prior to study entry are also excluded. Subjects who have not recovered from radiation, chemotherapy, or immunotherapy toxicities. Subjects with either previously irradiated or new CNS (central nervous system) metastases. (Pre-enrollment head CT is not required.) Subjects with a history of autoimmune disease such as, but not restricted to, inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis, scleroderma, or multiple sclerosis. Subjects with serious intercurrent chronic or acute illness such as pulmonary [asthma or chronic obstructive pulmonary disease (COPD)] or cardiac (NYHA class III or IV) or hepatic disease or other illness considered by the P.I. to constitute an unwarranted high risk for investigational drug treatment. Medical or psychological impediment to probable compliance with the protocol. Concurrent second malignancy other than non-melanoma skin cancer, or controlled superficial bladder cancer. In the event of prior malignancies treated surgically, the subject must be considered NED (no evidence of disease) for a minimum of 3 years prior to enrollment. Subjects on steroid therapy (or other immunosuppressive agents such as azathioprine or cyclosporine A) are excluded on the basis of potential immune suppression. Subjects must have had 8 weeks of discontinuation of any steroid therapy prior to enrollment. Presence of an active acute or chronic infection, including symptomatic urinary tract infection, HIV (as determined by ELISA and confirmed by Western Blot) or viral hepatitis (as determined by HBsAg and Hepatitis C serology). Subjects with penicillin allergies

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CV9103<br>CV9103 will be applied intradermally on three (3) or five (5) time points. Treatment with CV9103 is administered over a period of either seven (7) or twenty-three (23) weeks. | Biological: CV9103<br>* CV9103 encodes for 4 prostate specific antigens.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Assessment of Safety and Tolerability of the Trial Regimen | Dose Limiting Toxicity (DLT) is defined as the following treatment-related adverse events or laboratory abnormalities, graded according to NCI-CTCAE version 3.0: All Categories equal or greater than grade 3 Allergy/autoimmunity equal or greater than grade 2 Dosing delay greater than 48 hours due to toxicity All adverse events will be graded and documented according to Common Terminology Criteria for Adverse Events version 3.0. | At Nine Weeks with Follow Up at One Year |