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Open-label, Single-centre, Phase I, Multi-dose Escalating Study to Investigate the Safety and Preliminary Efficacy of an i.v. Infusion of the Anti-GRP78 Monoclonal IgM Antibody PAT-SM6 in Patients With Relapsed or Refractory Multiple Myeloma

Phase 1
18 Years
Open (Enrolling)
Drug Safety

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Trial Information

Open-label, Single-centre, Phase I, Multi-dose Escalating Study to Investigate the Safety and Preliminary Efficacy of an i.v. Infusion of the Anti-GRP78 Monoclonal IgM Antibody PAT-SM6 in Patients With Relapsed or Refractory Multiple Myeloma

Open-label, single-centre, dose escalation phase I study designed to investigate the safety
and tolerability of intravenous (i.v.) infusions of PAT-SM6 administered over 90 minutes.

A screening examination will be performed within 14 days prior to dosing. Eligible subjects
will receive 4 doses of PAT-SM6 (cycle 1: Day 1 and Day 3, cycle 2: Day 8 and Day 10).
Subjects will be hospitalised for at least 48 hours after each dose administration (i.e.
from Day 1 to Day 5 in cycle 1 and from Day 8 to Day 12 in cycle 2). During hospitalisation
subjects will be under constant surveillance. Subjects will return for ambulatory visits on
Days 15, 22, 29 and 36 for safety, pharmacokinetic (PK) and pharmacodynamic (PD)

Serological staging will be performed at baseline, on Day 29 (+/- 2 days) and Day 36 (+/-2
days). Response will be assigned by the International Myeloma Working Group (IMWG) uniform
response criteria for multiple myeloma. Complete response (CR) will be confirmed by bone
marrow aspiration; CT scans or other radiograph are only intended when clinical symptoms are
suspicious for progressing disease or otherwise clinically indicated.

If a subject shows an at least partial response (PR) on Day 29 or Day 36 (4 doses) the
sponsor discusses with the Data Safety Monitoring Board (DSMB) to give an additional 2 doses
(therefore the maximal number of doses for each subject is 6 doses) and a further staging
will be performed 14 and 21 days after the last dose administration.

A completion visit will be performed 4 days after the last serological staging (e.g. after
cycle 2 on Day 40).

Four dose groups (cohorts) are planned: 0.3 mg/kg followed by doses of 1 mg/kg, 3 mg/kg and
6 mg/kg. Subjects will be enrolled in a strict sequential order.

Individual safety results obtained until Day 5 will be evaluated by the investigator and the
sponsor before the next subject of the same dose group will be treated. After completion of
all 3 subjects of a dose group, safety results of all subjects obtained until Day 15 will be
reviewed by the DSMB and a decision for dose escalation will be made. Interim doses can be
administered if the increase is thought to be too high.

Subjects who show definite signs of progressive disease including hypercalcemia, new
osteolytic lesions or new soft tissue plasmocytoma will be withdrawn from the study at any

In case dose limited toxicity (DLT) was seen in a subject, further dosing of subjects in the
same dose group will be discussed with the DSMB, in case of a second DLT in the same dose
group dose escalation will be stopped and the study will be continued at the next lower
intermediate dose level or the previous tested dose will be regarded as the maximum
tolerated dose (MTD). The MTD is defined as the dose level below the dose inducing a DLT in
2 subjects within one dose level.

Inclusion Criteria:

- Male or female subjects ≥ 18 years of age

- Relapsed or refractory multiple myeloma defined as: Failure of at least 2 previous
therapies including an immunomodulatory agent (thalidomide or lenalidomide) and a
proteasome inhibitor (unless the subjects were not eligible or refused to receive
those treatments), and with progressive disease, defined by an increase of
serological or urine myeloma parameters by 25% to the last value

- Presence of serum M-protein ≥ 1 g per 100 mL (≥ 10 g/L) and/or urine M-protein ≥ 200
mg per 24-hour period and/or serum FLCs ≥ 10 mg per 100 mL (≥ 100 mg/L) combined with
an abnormal ratio of lambda and kappa chains

- Life expectancy of > 6 months

- Karnofsky performance status ≥ 60%, Eastern Cooperative Oncology Group (ECOG)
performance status ≤ 2.

- Absolute neutrophil count (ANC) ≥ 1.0 (1,000/mm3) and platelets ≥ 30 × 109/L without
previous transfusion within the last 2 weeks before first study drug administration

- Creatinine clearance ≥ 30 mL/min (calculated using the Cockcroft-Gault equation)

- Total bilirubin ≤ 2 × upper normal limit (UNL)

- Alanine transaminase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × UNL

- Haemoglobin ≥ 8 g/dL

- If a female of childbearing potential, confirmation of a negative pregnancy test
before enrolment and use of double-barrier contraception, oral contraceptive plus
barrier contraceptive, or confirmation of having undergone clinically documented
total hysterectomy and/or oophorectomy, tubal ligation

- If a male, use of an effective barrier method of contraception during the study and
for 3 months after the last dose if sexually active with a female of childbearing

- Ability to comply with all study-related procedures, medication use, and evaluations

- Ability to understand and give written informed consent, and comply with the protocol

Exclusion Criteria:

- Primary refractory multiple myeloma

- Previous treatment with cytotoxic chemotherapy or large-field radiotherapy or other
myeloma-specific therapy within 28 days prior to the screening visit (radiation to a
single site as concurrent therapy is allowed)

- Treatment with a systemic investigational agent within 28 days prior to the screening

- Hypercalcemia (> 2.7 mmol/L)

- Extramedullary plasmocytoma not originating from bone or plasma cell leukaemia

- Previous allogenic stem cell transplantation

- Known or suspected hypersensitivity to the excipients contained in the study drug

- Significant uncontrolled cardiovascular disease or cardiac insufficiency (New York
Heart Association (NYHA) classes III-IV)

- Prior therapy with other monoclonal antibodies

- Clinical or laboratory evidence of active hepatitis B (positive HBsAg with negative
HBsAb) or hepatitis C (positive hepatitis c virus antibody and detectable hepatitis C
virus RNA with ALT above the normal range)

- Positive HIV test result (ELISA or Western blot)

- History of ischemic colitis, stroke or myocardial infarction within the last 6 months

- Presence of diarrhoea of grade 2 or higher

- Any active uncontrolled systemic infection

- Any antibiotic therapy due to infections 2 weeks prior to first study drug

- Regular dose of corticosteroids during the 2 weeks prior to study entry or
anticipated need of corticosteroids exceeding prednisone 20 mg/day or equivalent, or
any other immunosuppressive therapy within 2 weeks prior to study entry.

- Major surgery ≤ 4 weeks prior to first study drug administration or ongoing side
effects of such surgery

- Systemic diseases (cardiovascular, renal, hepatic, etc) that would prevent study

- Multiple myeloma with central nervous system involvement.

- Second active malignant disease, currently requiring treatment (with the exception of
basal cell carcinoma of the skin or curative surgery treated tumours).

- Pregnancy or breastfeeding in women and women of childbearing potential not using an
acceptable method of birth control

- others

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Overall frequency of adverse events (AEs) (clinical symptoms, laboratory abnormalities, serious adverse events (SAEs) and treatment limiting adverse events)

Outcome Time Frame:

14 days

Safety Issue:


Principal Investigator

Max Top, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Universitätsklinikum Würzburg, Medizinische Klinik und Poliklinik II, Zentrum für Innere Medizin,


Germany: Paul-Ehrlich-Institut

Study ID:




Start Date:

October 2012

Completion Date:

March 2014

Related Keywords:

  • Drug Safety
  • Multiple Myeloma
  • Neoplasms, Plasma Cell