Principal objectives: •To determine the safety, tolerability and recommended dose of FP- 1305 in subjects withadvanced solid tumours of the selected tumourtypes without standard treatment options.• To determine the safety, tolerability and early…
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- Miscellaneous and site unspecified neoplasms malignant and unspecified
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Intervention
Outcome measures
Primary outcome
Part I
• Tolerable dose(s) was determined by the TITE-CRM based on the
occurrence/non-occurrence of dose limiting toxicities (DLT) in the trial
subjects.
Part II
• Safety and tolerability will be defined by physical examination, adverse
events and by safety laboratory tests. Adverse events are collected, graded and
reported according to the NCI-CTCAE version 5.0. Medical Dictionary for
Regulatory Activities (MedDRA) terminology will be used to classify, record,
manage, and analyse the data. Tolerability of new dose(s) will be determined
based on the occurrence/non-occurrence of DLT during 28 days following the
first dose of FP-1305 in subjects evaluable for DLT assessment in Part II.
• The ORR, CBR and irORR (separetely) to the treatment will be determined by
tumour imaging according to Response Evaluation Criteria In Solid Tumors
(RECIST) 1.1 based on images obtained during Cycle 7. The clinical benefit rate
(CBR) is the proportion of subjects that have a complete response (CR), partial
response (PR), or stable disease (SD). The irORR will also be calculated.
Results from each tumour type, dose level and dosing frequency will be
reported separately.
Part III
• The ORR, CBR and IrORR (separetely) to the treatment will be determined by
tumour imaging according to RECIST 1.1 based on images obtained during Cycle 7.
Results from each tumour type will be reported separately.
Secondary outcome
Secondary outcome measures:
Part I
• The PK profile of a single dose (during Cycle 1) and repeated doses (during
Cycles 1-5) of FP 1305 was determined by repeated measurements of the drug
concentration in the circulation. Peak concentration (Cmax), trough
concentration (Cmin), area under the plasma concentration versus time curve
(AUC), clearance, volume of distribution, and terminal half-life (t1/2) for
each dose level was determined.
• Immunogenicity was evaluated by assessing anti-drug antibodies in the
circulation periodically during treatment and follow-up.
• The ORR to the treatment was determined by tumour imaging according to RECIST
1.1. The CBR is the proportion of subjects that have a complete response,
partial response, or stable disease. The irORR was also calculated.
Part II
• The PK profile of a single dose (during Cycle 1) and repeated doses (during
Cycles 2-5) of FP 1305 will be determined by repeated measurements of the drug
concentration in the circulation. Peak concentration (Cmax), trough
concentration (Cmin), AUC, clearance, volume of distribution, and terminal
half-life (t1/2) for each dose level will be determined. Results from each
tumour type will be reported separately.
• Immunogenicity will be evaluated by assessing anti-drug antibodies in the
circulation periodically during treatment and follow-up. Results from each
tumour type will be reported separately.
• Potential genetic, cellular and other predictive markers will be associated
with FP 1305 clinical activity as determined by ORR, CBR and irORR. This
includes but not limited to the correlation of response and immune cell
profile, cytokine/chemokine profile and the proportion of CLEVER 1-positive
monocytes; Cluster of Differentiation (CD)4, CD8, their ratio and regulatory T
cells in the circulation and in tumour specimens prior to treatment and in
circulation during the first cycle of treatment.
• The duration of response is measured from the time of initial response until
documented tumour progression, death, or dropout.
• Safety and tolerability will be defined by physical examination, adverse
events and by safety laboratory tests. Adverse events are graded and reported
according to the NCI-CTCAE version 5.0. MedDRA terminology will be used to
classify, record, manage, and analyse the data.
Part III
• The population PK of FP 1305 will be determined by measurements of the drug
concentration in the circulation between Cycles 1 and 5. Results from each
tumour type will be reported separately.
• Immunogenicity will be evaluated by assessing anti-drug antibodies in the
circulation periodically during treatment and follow-up. Results from each
tumour type will be reported separately.
• The duration of response is measured from the time of initial response until
documented tumour progression, death, or dropout.
• Progression free survival as the time from subject allocation into the trial
until documented disease progression according to RECIST 1.1 or death will be
measured in the population that has been dosed at least once.
• Overall survival is defined as the time from subject allocation into the
trial until death from any cause and will be measured in the population that
has been dosed at least once. Data will be censored on the last documented data
that the subject has been alive.
• Safety and tolerability will be defined by physical examination, adverse
events and by safety laboratory tests. Adverse events are graded and reported
according to the NCI-CTCAE version 5.0. MedDRA terminology will be used to
classify, record, manage, and analyse the data.
Background summary
This is a first in human study to identify whether FP-1305 is suitable to use
in oncology patients. The previous pre-clinical studies have demonstrated that
FP-1305 binds to a receptor known as CLEVER-1. CLEVER-1 has been shown to
support tumour growth. No significant adverse events were witnessed in primates
and the dose used will be 300 fold lower than the dose provided to primates
which showed no toxicity.
Based on our existing data CLEVER-1 is expressed in these tumour types.
Inhibition of CLEVER-1 with FP-1305 may have an anti-tumour effect in these
patients.
Subject safety will be closely monitored after the first infusion and regularly
throughout the trial. In Part 1, only a single patient at a time was dosed on a
new dose level. Dose is escalated step wise once lower dose has been
demonstrated safe in study subjects. Dose level is raised until the maximum
tolerated dose is reached.
The proposed trial design enables a flexible approach to identify a safe and
tolerable dose which has a biological effect and to expand the cohorts of
different tumour types after the dose has been selected. Analysis of the
primary efficacy in the expansion cohorts early enough with sufficient
statistical power allows for a rapid adaptation of the protocol in order to
focus on the tumour types in which the treatment demonstrates the most
promising activity.
In addition to the Q3W dosing, Protocol Addendum introduces once in two weeks
(Q2W) and once in week (Q1W) dosing schemes to be investigated in the Part II
of the study. The scientific rationale for investigating more frequent dosing
(Q2W and Q1W) is based on Part I PK and receptor occupancy of the CLEVER-1
(refer to Investigator*s Brochure).
During Part II, additional dose levels are tested to investigate tolerability
and safety in a broader dose range, and to receive additional data about the
PK, RO and preliminary efficacy. The selected doses are 30 mg/kg and 100 mg/kg;
other intermediate doses (below 100 mg/kg) may be included if deemed necessary
based on accumulated data. The scientific rationale for investigating higher
doses (30 mg/kg and 100 mg/kg) is based on the cumulative study data, e.g. PK
(relatively fast T1/2) and RO (transient) of the CLEVER-1 at dose levels of 0.1
- 10 mg/kg (refer to Investigator*s Brochure), and accumulated safety data
indicating good tolerability of the IMP and no DLT events registered.
Inclusion of multiple distinct cancer types to the first cohort of ten subjects
at a new dose level is possible, justified by allowing the investigation of the
safety of the dose level in a wider population than just one particular cancer
type in Part II. However, if deemed necessary, multiple cohorts with distinct
cancer types may be selected to be explored at a dose level (and at more
frequent dosing). This approach is justified by allowing the investigation of
the safety and preliminary efficacy properly in Part II, as distinct cancer
types may respond differently to the treatment.
Study objective
Principal objectives:
•To determine the safety, tolerability and recommended dose of FP- 1305 in
subjects withadvanced solid tumours of the selected tumour
types without standard treatment options.
• To determine the safety, tolerability and early efficacy of FP-1305 therapy
alone by using measures known as the objective response rate (ORR) (which
measures the portion of patients with tumour shrinkage over a period of time),
Clinical Benefit Ration (CBR) and immune-related ORR (irORR) (same as above but
with particular immune response focus) in distinct groups of subjects with
advanced solid tumours of the selected tumour types.
• To assess the objective response rate (ORR, CBR and irORR) in distinct
expansion groups of subjects with advanced solid tumours in subjects who show
presence of CLEVER-1 molecule from selected tumour types at a selected dose.
Secondary objectives:
To study Pharmacokinetics (drug activity) after different doses
• To assess the immune response to FP-1305
• To understand pharmacokinetics and the anti-drug antibodies (immune system
produces a response to the drug to disable it) in different tumour types
• To determine the presence of CLEVER-1 molecule in patients
• To assess ORR & duration of response in different tumour types
• To study Progression free Survival and Overall Survival
Study design
This is a first in human study to determine the safety, tolerability and
preliminary efficacy of FP-1305 administered in three week intervals in
addition to 2 week and single week intervals. Each interval is known as termed
a cycle.
The study is made up of 3 parts:
Part I: aimed to escalate the dose at defined levels and was aimed to determine
the maximum tolerated dose in trial subjects with selected solid tumours. At
each dose level, the first patient was observed for the full cycle before a
second patient was introduced. This was repeated until the highest dose was
reached. Following some statistical analysis, further doses might be opened up
to determine the dose to be used in Part II. This is now complete.
Part II: following a review of Part I, tumour types will be selected for
expansion of patient numbers. The study will continue in these populations for
approximately a year. The dose is selected based on Part I.
Part II has been expanded to include more dosage levels and also more frequent
dosing.
Part III: Following further reviews, the tumours with best response according
to (Objective Response Rate) ORR will be further expanded to more patients.
For each part of the study, there will be a screening period, a treatment
period with FP-1305 that will last as long as the doctor thinks FP-1305 is
helping the patient (for a maximum of one year), and a follow-up period, that
will last a maximum of 4 weeks after the patient stop treatment with FP-1305.
If the patient decides to take part in this study, the patient will first be
asked to sign and date this PICD.
The patient will then enter the Screening Period: This is usually done in one
day but may take up to 4 weeks.
During screening, the study doctor will assess whether the patient meet the
study requirements. The study doctor will ask the patient questions about
general health, the cancer, other past and ongoing illnesses, and the
medications the patient are taking, and other research studies the patient have
taken part in.
The patient will be asked for a few blood tests to test for any infections,
blood cells and blood chemistry. A pregnancy test will be requested if the
patient have the ability to become pregnant. If the patient has symptoms that
suggest the cancer has spread to the brain, the patient will be asked to go for
a brain scan.
If the study doctor determines that the patient meet the study requirements,
the patient will be eligible to participate in the study.
During the Treatment Period:
Part I and II are similar in terms of visit schedule however Part III has fewer
visits and will be highlighted below. The study will be divided in treatment
cycles that last approximately 3 weeks each. On the first day 1 (D1) of each
cycle the patient will receive FP-1305.The treatment may be continued after one
year based on the consideration on the investigator.
Part II has been expanded to more frequent dosing and thus Q2W and Q1W have
more visits.
FP-1305 will be given to the patient on the first day of every cycle,
approximately every 3 weeks for as long as the study doctor thinks FP-1305 is
helping the patient (for a maximum of one year).
Throughout the study the patient will be regularly asked about the general
health, any other medications the patient are taking and any side effects or
complications that may occur while the patient receive FP-1305.
During Follow-up:
After the patient have finished receiving FP-1305 treatments, the patient will
be invited for a follow-up visit approximately 3 weeks later.
The follow up visit will approximately take 3 hours.
the study doctor will check the general healthy by doing a physical examination
and doing some blood test.
The care of the subject should follow clinical routines. However, treatment can
continue beyond one year, if beneficial for the study subject, as judged by the
investigator (and provided that the clinical development and manufacturing of
FP-1305 continues and it is not available via other routes). In such case, the
data collection is limited to the collection of treatment related adverse
events (disease progression will be collected through AE reporting) and overall
survival.
Intervention
Non clinical interventions/procedures:
Main Study Informed Consent,
Genetic data informed consent,
Review of Inclusion/Exclusion Criteria,
Demographic data and medical history,
Concomitant medications
Clinical interventions/procedures:
Height, Weight and Physical
Vital Signs
ECG
ECOG
Urine dispstick test (parts I and II)
Pregnancy test
Blood sampling (various including PK) for Part I, II and III
Tumour Biopsy
Tumour imaging
Brain Imaging
Study burden and risks
The study is a first in human study, hence the safety profile is to be
developed. Throughout the study the health of the subject will be regularly
monitored and appropriate medical intervention will be available if required.
Because of this, the only information on side effects comes from studies in
animals.
In animals given higher doses than what you will receive, scientists have seen
possible damage to the liver. This will be monitored closely by the various
blood tests and will be minimised as only one patient will be on each dose
level for 3 week period to allow sufficient monitoring.
FP-1305 stimulates the immune system, it is possible that the patient might
experience a general body reaction from the infusion. This includes difficulty
breathing, low blood pressure high blood pressure, headache, skin rashes and
increased temperature. This again will be monitored closely by the study team
and treated accordingly.
Electrocardiogram (ECG)
This test is also non-invasive and not painful. The electrocardiogram (ECG) is
a tracing of patients heart beating, made by recording tiny changes of
electricity produced by their heart at the surface of the skin. To record these
changes electrode stickers will be put on patients chest with wires attached to
them. It will take about 5-10 minutes
Blood sample analysis
Blood samples will be collected for examination at each visit. Collecting the
blood samples might cause discomfort during the study. An anaesthetic cream can
be apply to make the area numb and reduce the discomfort.
Taking a tissue biopsy can be painful and carry a risk of swelling, bleeding
and infection in the organ from where the biopsy is taken. There are other
risks that depend on where the tumour is in the body, for example, the lungs,
the liver, the gut, or the skin. This is part of routine care, while in the
study this could be more frequent than usual, the medical team will be suitably
trained for this task.
CT Scan: The is a risk of generalized body reaction form the contrast agent
used to get special images from the CT scan. This includes potential damage to
the kidneys. The patient will be monitored closely during the procedure.
The MRI scan makes noise, and leave little space for movement, so the patient
may feel anxious during the test. The patient will be monitored throughout the
procedure.
Study visits: frequency and duration: The frequency and duration of study
visits might have an impact on the participant daily life
Joukahaisenkatu 6
Turku FI-20520
FI
Joukahaisenkatu 6
Turku FI-20520
FI
Listed location countries
Age
Inclusion criteria
1) Written Informed Consent
2) Aged >= 18 years male or female
3) Tumour sample should be collected during screening period. If a recent
tumour biopsy obtained within six months before the date of consent is
available (or older, as agreed on a case by case basis with the sponsor), that
may be used. At the discretion of the sponsor, the tumour sample may be
optional for certain subjects in Part III
4) Life expectancy > 12 weeks
5) Histologically confirmed advanced (inoperable or metastatic) malignancies in
which (according to the view of the investigator) no curative, effective or
suitable treatment options exist:
o Hepatocellular carcinoma
o Gallbladder cancer or intra- or extrahepatic cholangiocarcinoma
o Colorectal adenocarcinoma
o Serous poorly differentiated (Grade 3) ovarian adenocarcinoma or
undifferentiated ovarian cancer
o Pancreatic ductal adenocarcinoma
o Immunotherapy (IO) resistant cutaneous melanoma (progression during
programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1)
or cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody therapy)
o Uveal melanoma in Parts II and III
o Gastric adenocarcinoma (including adenocarcinoma of the distal esophagus / GE
junction) in Parts II and III
o ER+ breast cancer in Parts II and III
o Anaplastic thyroid cancer in Parts II and III
6) ECOG performance status 0 or 1
7) Measurable disease in Parts II and III
8) Adequate bone marrow, liver and kidney function defined as
Blood white blood cell >= lower limit of normal
Blood neutrophil count >= 1x109/L Blood platelet count >= 100x109/L, for HCC >=
50x109/L
Blood haemoglobin >= 9.0 g/dL
Creatinine clearance > 40 mL/min calculated by Cockcroft-Gault
formula AST <= 3 X ULN (<= 5 x ULN when HCC or hepatic metastases are
present)
ALT <= 3 X ULN (<= 5 x ULN when HCC or hepatic metastases present)
Bilirubin <= 1.5 X ULN
Albumin >= 3.0 g/dL
The most recent measurements taken during the screening period must be within
the required limits for the patient to be considered eligible (i.e. criteria
met once during the screening period are not sufficient if there are more
recent measurements available that are not within the required
limits. It is however acceptable to repeat measurements if the initial
measurements or subsequent measurements taken during the screening period are
not within the required limits; the patient is eligible providing that the
newest measurements are within the required limits). However,
once a subject is out of the screening period, and has had eligibility
confirmed and been enrolled, the pre-dose laboratory assessments are not
subjected to inclusion criteria limits, but only for investigators assessment
of subject safety.
9) Women of child-bearing potential must have a negative pregnancy test in
serum prior to trial entry
10) Women of child-bearing potential and men who have partners of child-bearing
potential must be willing to practise highly effective contraception for the
duration of the trial and for three months after the completion of treatment
Exclusion criteria
1) Less than 21 days since the last dose of intravenous anticancer chemotherapy
or less than five half-lives from a small molecule targeted therapy or oral
anticancer chemotherapy before the first IMP administration
2) Any immunotherapy within preceding 6 weeks from the first IMP administration
3) Investigational therapy or major surgery within 4 weeks before the first IMP
administration
4) Active clinically serious infection > Grade 2 NCI-CTCAE version 5.0 within
preceding 2 weeks before first IMP administration
5) Brain metastases
6) Subject has not recovered from the previous therapies to Grade <= 1 severity
as classified by the NCI-CTCAE version 5.0 (except Grade <= 2 alopecia,
neuropathy or thyroid disorders)
7) Pregnant or lactating women
8) History of second malignancy except for non-melanotic skin cancer, cervical
carcinoma in situ or superficial bladder cancer, or any other malignancy
treated previously with curative intent and more than three years without
relapse
9) Evidence of severe or uncontrolled systemic diseases, congestive cardiac
failure New York Heart Association class >= 2, Myocardial Infarction within 6
months or laboratory finding that in the view of the investigator makes it
undesirable for the subject to participate in the trial
10) Any medical condition that the Investigator considers significant to
compromise the safety of the subject or that impairs the interpretation of IMP
toxicity assessment
11) Confirmed human immunodeficiency virus infection
12) Symptomatic cytomegalovirus infection
13) Subjects with active auto-immune disorder (except type I diabetes, celiac
disease, hypothyroidism requiring only hormone replacement, vitiligo,
psoriasis, or alopecia)
14) The subject requires systemic corticosteroid or other immunosuppressive
treatment
15) Subjects with organ transplants
16) Subjects in dialysis
17) Use of Live (attenuated) vaccines for 30 days prior to the start of study
treatment, during treatment, and until last visit
18) Subject is unwilling or unable to comply with treatment and trial
instructions
19) Subjects with known hypersensitivity to the IMP or any of the
pharmaceutical ingredients
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-002732-24-NL |
| ClinicalTrials.gov | NCT03733990 |
| CCMO | NL67687.078.19 |