Study rationale with regard to patient populations and test drug

      CRCP is an aggressive malignant disease with poor prognosis after failure of established
      therapies. Any drug employed after third-line treatment is associated with only limited
      clinical benefit. Therefore, there is a high medical need for new therapeutic approaches in
      this patient population. While progress has been made in the field of immunotherapeutics for
      other tumor types, no relevant progress in immunotherapeutic options in CRPC has been
      achieved over the last years. The rationale for the therapeutic use of CC-1 is based on its
      proposed mode of action as a bsAb being specifically designed to direct T cells via its CD3
      binding part towards tumor target cells via its PSMA binding part. Furthermore, CC-1 also
      reacts with tumor vessels of CRPC thereby allowing for a dual mode of anti-cancer action by
      also attacking tumor blood supply and allowing for improved influx of immune effector cells.
      Due to its unique ability to redirect T cells via CD3 for PSMA-expressing tumor cell lysis,
      CC-1 can elicit repeated target cell elimination by cytotoxic T cells and a polyclonal
      response of previously primed CD4+ and CD8+ T cells. Compared to other immunotherapeutics
      presently being approved or in development (bsAbs with alternative formats like the
      authorised bsAb blinatumomab or other antibodies or CART cells), CC-1 is expected to offer
      the following major advantages:

      (i) Reduction of off-target T cell activation and thus reduction of side effects due to its
      optimized format (ii) The possibility to tightly steer anti-target activity via serum
      level-controlled antibody application which, in contrast to CART cells, allows for
      termination of activity if desired.

      On the background of the poor prognosis of patients with CRPC after third-line therapy, the
      bsAb CC-1 holds promise as a new treatment option of immunotherapy for these patients.

      Study rationale with regard to objectives and further development of CC-1 In nonclinical
      studies, in vitro and in vivo, proof of concept, preliminary PK and PK/PD effects as well as
      toxicology have been evaluated as described in detail in the IB, section 5. However, due to
      differences between animal models and the human situation, some aspects have to be assessed
      and further characterised in humans. For example, the target mediated drug disposition
      (TMDD), an effect that largely influences the serum half-life of antibody molecules
      particularly at low concentrations, cannot be properly addressed in mice. Furthermore,
      nonhuman primates (NHP) and rodents have several limitations as predictive models for
      toxicity and immunogenicity evaluation of CC-1. The CD3 binding part of CC-1 does not
      cross-react with CD3 of macaques and thus it is not possible to evaluate in these NHPs dose
      limiting side effects. Likewise, although CC-1 is cross-reactive with macaque-PSMA, PSMA
      distribution in macaques significantly differs from that in humans. The same holds true for
      rodents. Therefore, a First in Human study is planned for CC-1 to overcome these limitations
      and to characterise the effects of CC-1 in humans.

      The planned phase I trial is designed to confirm and further explore the safety and
      tolerability of the PSMAxCD3 bsAb CC-1 in adult patients with CRPC after third-line therapy.
      The primary objective is incidence and severity of adverse events (AEs) under therapy with
      CC-1. Furthermore, the trial aims to expand experience on pharmacokinetics, pharmacodynamics
      and toxicology of CC-1 from nonclinical studies to the human situation in relation to the PK,
      expected efficacy and safety. A focus will be on the following specific aspects/parameters:

        -  Pharmacokinetics and pharmacodynamics of CC-1 in humans

        -  Immunogenicity of CC-1 in humans based on both absolute (number and percentage of
           subjects who develop human anti-human antibody (HAHA).

        -  Absolute changes from baseline in the tumor marker (PSA)

        -  Absolute changes from baseline in laboratory parameters

        -  Change in cytokines from baseline

        -  Assessment of response rate by ReCist on routine imaging

        -  Overall and progression free survival

      Rationale for preemptive IL-6R blockade by Tocilizumab prevent development of CRS in the
      first place than to treat CRS once it has arisen. This strategy holds promise to increase the
      safety of study patients and timely study conduct.

      By starting the study treatment with CC-1 directly with prophylactic tocilizumab, all study
      patients will benefit from the expected advantage of this combination with regard to safety
      and can be treated with sufficiently high doses of CC-1 to achieve dose levels high enough to
      hopefully result in efficacy effects.The rationale for preemptive IL-6R blockade by
      tocilizumab treatment is based on i. The firmly established efficiency and safety of
      tocilizumab for the treatment of CRS ii. Lack of clear evidence for increased tumor growth as
      potential drawback of IL-6R blockage iii. Observations that IL-6 activity, while being
      responsible for the undesirable sequelae of CRS, appears not to be required for the
      therapeutic activity of CC-1 CRS that was induced by therapy with the approved bsAb
      blinatumomab was reported to be successfully treated by tocilizumab. Most importantly,
      despite rapid disappearance of clinical CRS symptoms, the therapeutic activity of the bsAb
      blinatumomab was maintained. Furthermore, tocilizumab was also used in the very recent FIH
      study with the REGN1917 (CD20xCD3) antibody (Bannerji et al., 2018). Our own nonclinical
      studies demonstrate that tocilizumab does not impair the therapeutic activity of CC-1,
      neither in vitro nor in vivo. This is in contrast to steroids which are currently recommended
      and used as pre- and concomitant treatment to prevent CRS upon blinatumomab therapy. Due to
      the mechanism of action of tocilizumab, there is a theoretical risk of tumor development or
      tumor progression due to immune modulation. On the basis of the current literature derived
      from large studies conducted in Japan, the USA and Europe, however, there is no evidence for
      an increased tumor risk upon application of tocilizumab. Only one Japanese study described a
      minimally increased risk of de novo lymphoma development. However, this could not be
      confirmed in any other study. Especially for prostate cancer, there is no evidence for an
      increased incidence rate. Furthermore, tocilizumab is currently being investigated in several
      Phase I/II studies for the treatment of solid and hematological neoplasias without available
      evidence for an influence on tumor pathophysiology. Based on these findings, no relevant
      negative effects of tocilizumab on the efficacy and safety of CC-1are expected.

      Trial Duration and Schedule A treatment cycle consists of 21 days, comprising 7 days (d1-7)
      of CC-1 application as continuous infusion, followed by a treatment free period with further
      close monitoring for safety. The duration of the trial for each patient is expected to be at
      least 3 months including the first treatment cycle of 21 days and a safety follow-up on day
      90 (end of study, EOSf). Thereafter, a continuous survival follow-up every three months is
      conducted for one year after EOSf. In case of clinical benefit, treatment period can be
      longer.

      Screening period, enrollment and baseline The screening period is part of the study and
      begins 14 days prior to first treatment. The patient is informed about the study by the
      investigator and has to sign informed consent. In the following, further measures and
      analyses are performed to check whether the patient meets all inclusion/exclusion criteria.
      If a patient meets all criteria, he is enrolled in the study. If he does not meet all
      criteria, he is not enrolled but documented as a screening failure.

      Baseline values are the following:

        -  Routine imagingimaging and analysis of HAHA are both assessed in the screening period
           (up to day -14).

        -  Baseline values for Quality of Life are assessed in the screening period (up to day -14)

        -  Baseline values for PSA, cytokines, pharmacokinetics and liquid biopsy are taken
           directly before start of CC-1 infusion (on day 1)

        -  Baseline values for hematology and blood chemistry as well as coagulation parameters are
           taken directly before start of CC-1 infusion (on day 1)

        -  Baseline for signs and symptoms of disease as well as vital signs (for evaluation of
           CRS) are documented directly before start of CC-1 infusion (on day 1)

      Treatment Cycle Each treatment cycle of an individual patient is 21 (±2) days. Every cycle
      comprises a treatment period (d1-7) with a continuous infusion (daily) of CC-1 after
      preemptive tocilizumab application and an infusion free period (d8-21). While for d1-9 the
      patients are hospitalized and closely monitored, day 10-21 is planned as outpatient period
      with outpatient self-monitoring and visits at the hospital at d15 and d21 (EOT). Discharge of
      the patient is planned at day 9 but depending on the patient´s condition. At the discretion
      of the physician, the patient can be also discharged at day 10 (or later). Justification of
      continuous infusion Continuous infusion has been utilized in several phase I/II studies with
      the bsAb blinatumomab: In a phase I/II study in children with refractory ALL, blinatumomab
      was applied as 24 continuous infusion over 4 weeks. A 24h continuous infusion of blinatumomab
      was also applied in first investigations in adults (NCT00274742) as well as in a phase II
      study in adults with refractory B-ALL. Overall, continuous infusion is expected to provide
      reasonable safety due to avoidance of peak serum levels with subsequent rapid decline.

      Justification of length of treatment (infusion) with CC-1: A treatment duration of 7 days was
      chosen for the following reasons:

      It is expected that no maximum tolerated dose (MTD) will be identified in the dose expansion
      phase and that patients will receive the maximum tested dose. At higher dose levels, for
      reasons of safety we implemented step dosing on day 1 and day 2 of each cycle followed by
      application of the target dose (to be determined, possible maximum tested dose) over 5 days.
      This is based on our published observations that CD3-mediated activation of T cells within
      PBMC populations in vitro requires 3 days until full activation is achieved. Notably, in
      these in vitro analyses high antibody concentrations (3μg/ml and thus several orders of
      magnitude more than those that will be achieved in our study patients) were utilized. It was
      also observed in a previous study that the presence of human serum reduces CD3-mediated T
      cell activation. For these reasons, we conclude that exposure to active drug levels for
      additional 2 days (and thus 5 days in total after day 2) may ascertain optimal T cell
      activation.

      Justification of length of cycle:

      A cycle length of 21 days was chosen for the following reasons:

      The calculated half-life in mice of about 48h is based on the simplified assumption of an
      exponential decline within the first 24h. Thereafter serum concentration declined at a slower
      rate indicating a biphasic elimination. For calculation of the cycle interval we therefore
      assumed a half-life of 48h. Considering that CC-1 application is completed on day 8, a margin
      of 5 half-lifes (equaling to 10 days) results in an overall interval of 18 days.
      Additionally, based on our reported findings that after achieving maximal T cell activation a
      decline of activity over 3 further days is observed, for reasons of safety we plan to allow
      for 3 additional days until the end of treatment (EOT) visit is conducted (18 plus 3 days)
      and treatment can potentially be repeated. Notably, in the dose escalation cohort, approval
      of the DSMB is required before a new patient can be treated with the next dose level, for
      which we calculate an additional 7 days. Thus, a second cycle of treatment can be applied at
      day 21 to the same patient, but treatment of new patients, for reasons of uniformity, is
      generally conducted at day 28 of the antecedent patient at the earliest.

      Additional Cycles It is assumed that additional treatment cycles do not increase the risk but
      would rather benefit patients. Therefore, in case of positive response, the patient is
      allowed to continue treatment with up to 5 further treatment cycles. This is intended to
      allow patients to benefit better from therapy in case it is effective. Positive response to
      CC-1 treatment in previous cycle comprises (but is not limited to) a substantial PSA drop
      (>20% reduction compared to day 1 pretreatment as determined on day 15). To obtain additional
      cycles, patients must still meet the initial key eligibility criteria assessed between 6-8
      days prior to the next cycle (excluding cardiac ultrasound, lung function, virology,
      tuberculosis testing, CT/MRI imaging). Patients are required to sign the informed consent
      form for additional CC-1 cycles. Study visits and investigations are performed as described
      for the first cycle of CC-1 treatment. This includes all obligations for safety-reporting and
      documentation. The dose of CC-1 in additional cycles is the same as in the patient´s first
      cycle. In case of additional cycles, the end of safety follow-up (EOSf) visit is prolonged to
      90 days after start of the last CC-1 cycle. Routine imaging is planned every 90 days (+/- 7
      days).

      Post-Treatment Follow-Up until End of safety follow-up (EOSf)

      After the treatment cycle (s), follow-up of patients is planned as follows:

      After the last visit of the last treatment cycle at d21 (EOT), a follow-up visit is planned
      at d 90 (± 7) (69 days after EOT). In case of only one treatment cycle, this visit is the
      EOSf for this patient. This time point was chosen based on clinical practice and assessment
      according to RECIST criteria (see secondary endpoints). A comprehensive workup is planned on
      this visit. In case of additional cycles, the EOSf visit is prolonged to 90 days after start
      of the last CC-1 cycle.

      Follow-up after EOSf until EOS After EOSf, each patient is followed every 90 days (± 7) for
      up to one 1 year. EOS will be the last visit one year after EOSf, unless study treatment is
      terminated earlier.

      In case the patient is reported to have progressive disease on routine imaging, the
      investigator may decide to perform an additional visit 28-42 days later.

      Patient care after last follow-up After finishing all study-relevant procedures, therapy and
      follow-up period as described above, the patient are followed in terms of routine care and
      treated if necessary, by the primary responsible oncology center. Any attempt should be made
      by the investigator to follow the patient in particular with regard to any safety issues even
      after the last assessment at EOS.

      Estimated timelines The recruitment period may vary substantially based on observed
      toxicities, but is expected to be 2 years, and an overall study duration of 3.25 years is
      anticipated. Recruitment of patients starts in the fourth quarter of 2019