RNActive®-Derived Therapeutic Vaccine
RNActive®-Derived Therapeutic Vaccine
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.
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.
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