| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
- locally advanced or metastatic adrenocortical carcinoma (ACC)
- malignant pheochromocytoma/paraganglioma (MPP) |
|
| E.1.1.1 | Medical condition in easily understood language |
- locally advanced or metastatic adrenocortical carcinoma (ACC)
- malignant pheochromocytoma/paraganglioma (MPP) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10001388 |
| E.1.2 | Term | Adrenocortical carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10034876 |
| E.1.2 | Term | Pheochromocytoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10075444 |
| E.1.2 | Term | Malignant paraganglioma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of the phase 1 part of this trial is to evaluate
safety and tolerability of EO2401 in combination with nivolumab in
patients with unresectable, previously treated, and previously untreated,
locally advanced or metastatic ACC, and progressive MPP.
The primary objective of the phase 2 part of this trial is to determine the
effect of EO2401/nivolumab on the progression-free survival rate at 6
months, per investigator/local site assessments, for patients treated in
the randomized extension of Cohort 2A* (patients treated with EO2401
monotherapy and nivolumab monotherapy, respectively, will constitute
internal concurrent controls in the randomized extension).
* Cohort 2A = patients with ACC who had prior systemic therapy for
established locally advanced or metastatic disease |
|
| E.2.2 | Secondary objectives of the trial |
The key secondary objectives of the trial are:
- immunogenicity in relation to T cells of EO2316, EO2317, EO2318, and
UCP2 that compose EO2401; T cell cross-reactivity with the human TAAs
IL13Rα2, FOXM1, and BIRC5/surviving will also be evaluated,
The other secondary objectives of the trial are:
- objective response rate (ORR), time to response and duration of
response (DOR), and
- progression-free survival (PFS) and overall survival (OS).
- in addition, in the randomized extension of Cohort 2A safety and
tolerability of EO2401/nivolumab assessed versus internal concurrent
controls |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. For inclusion in Cohort 1 patients should have adrenocortical
carcinoma, or malignant pheochromocytoma/paraganglioma, as defined
below for Cohorts 2A and 3A.
2. For inclusion in Cohorts 2A and 2B patients should have histologically
confirmed (at primary diagnosis) unresectable locally advanced or
metastatic (ENSAT/AJCC] stage 3 = tumor has spread into nearby
tissues or lymph nodes, or stage 4 = metastatic disease) adrenocortical
carcinoma.
a. In addition, for inclusion in Cohort 2 A patients should also have
received treatment with at least one line, but not more than two prior
lines, of systemic therapy for established locally advanced or metastatic
disease (i.e. non-adjuvant therapy), and should within these lines of
therapy for advanced/metastatic disease, or as neoadjuvant/adjuvant
therapy, have received mitotane therapy delivered at an adequate dose.
b. In addition, for inclusion in Cohort 2B patients should not have
received prior systemic therapy for established locally advanced or
metastatic disease (i.e. non-adjuvant therapy).
Note, for both Cohorts 2A and 2B, neoadjuvant/adjuvant therapy
(including mitotane with or without chemotherapy) for patients after
complete response to local therapy should not be counted in the
definitions above for line of therapy for established disease. Patients
who have received mitotane as neoadjuvant/adjuvant therapy, or
therapy for advanced/metastatic disease can continue mitotane during
study therapy provided definitions regarding eligibility of continued
mitotane therapy are fulfilled.
3. For inclusion in Cohorts 3A and 3B patients should have histologically
confirmed (at primary diagnosis) unresectable malignant (defined as
metastatic disease, i.e. presence of chromaffin tissue in non-chromaffin
organs pheochromocytoma/paraganglioma, and RECIST defined
progression should have been documented during a maximum of an
18months period.
a. In addition, for inclusion in Cohort 3A patients should also have
received treatment with at least two prior lines of systemic therapy if
the patients are eligible for radionuclide therapy, and at least one prior
line of systemic therapy if the patients are not eligible for radionuclide
therapy.
b. In addition, for inclusion in Cohort 3B patients should not have
received prior systemic therapy for their malignant
pheochromocytoma/paraganglioma.
4. Patients with an age ≥ 18 years old.
5. Patients who are human leukocyte antigen (HLA)-A2 positive.
6. Patients with an Eastern Cooperative Oncology Group (ECOG)
performance status ≤ 1 with the specific meaning of ECOG 1 being
"restricted in physically strenuous activity but ambulatory and able to
carry out work of a light or sedentary nature, e.g. light house-work,
office work".
7. Patients with a life expectancy > 4 months as judged by their treating
physician.
8. Patients with at least one measurable lesion according to RECIST 1.1
(see Section 12.1).
9. Males or non-pregnant, non-lactating, females who are:
a) female, post-menopausal (serum follicle-stimulating hormone (FSH)
level > 40 mIU/mL),
b) female and male, surgically sterile (e.g. bilaterally blocked or
removed fallopian tubes, vas deferens),
c) female of childbearing potential with a negative highly sensitive
serum pregnancy test within 72 hours prior to first administration of
study treatment and use of a highly effective contraception from signing
the Informed Consent Form (ICF) through 5 months after the last study
treatment dose administered; note, the male partner should in addition
to the use of highly effective contraception by the female patient also
use condoms,
d) male patient with female partners of childbearing potential must use
condoms from signing the ICF through 5 months after the last study
treatment dose administered; in addition, male patients must ensure
that their partners of childbearing potential also use highly effective
contraception.
Highly effective contraception includes:
i) combined (estrogen and progesterone containing) hormonal
contraception associated with inhibition of ovulation: oral, intravaginal,
transdermal,
ii) progestogen-only hormonal contraception associated with inhibition
of ovulation: oral, injectable, implantable, intrauterine device, and
iii) sexual abstinence when in line with the preferred and usual lifestyle
of the patient (e.g. periodic abstinence is not considered a highly
effective method).
10. Patients willing and able to comply with the scheduled visits,
treatment plan, laboratory tests, and other study procedures indicated in
the protocol.
11. Patients having received the information sheet and who have
provided written informed consent prior to any study-related
procedures. Note, a 2-stage consent procedure is going to be used in the
trial (see Section 4.2); the first minimized consent related to the
procedure of HLA-testing, and the second to all other trial details and
procedures. |
|
| E.4 | Principal exclusion criteria |
1. Patients treated with dexamethasone > 2 mg/day or equivalent (i.e.
13 mg/day of prednisone, or 53 mg/day of hydrocortisone) within 14
days before the first EO2401 administration, unless required to treat an
adverse event. Note, inhaled steroids and adrenal replacement steroid
doses > 13 mg daily prednisone equivalents are permitted. Thus,
patients needing hydrocortisone replacement therapy due to prior or
ongoing mitotane therapy can receive hydrocortisone doses > 53
mg/day, i.e. also in the normally used range of 60-80 mg/day, and still
be included in the trial.
2. Patients with prior treatment with compounds targeting PD-1, PD-L1,
CTLA-4, or similar compounds where general resistance against
therapeutic vaccination approaches might have developed (e.g. defects
to the cellular antigen processing/presentation machinery, including
mutations in Janus kinas [JAK] 1, JAK2, and β-2-microglobulin [B2M])
allowing tumor cells to avoid recognition and attack by immune cells.
3. Patients with prior exposure to EO2401, e.g. patients treated in
Cohorts 2B or 3B of the current trial cannot be re-enrolled for treatment
also in Cohorts 2A or 3A.
4. Patients treated with immunotherapy (meaning immunostimulatory or
immunosuppressive therapy; beside excluded, or allowed, compounds
per other inclusion/exclusion criteria specifications), radionuclide
therapy, radiotherapy, cytoreductive therapy, or received treatment with
any other investigational agent within 28 days before the first EO2401
administration. Note, for patients with ACC continued treatment with
mitotane during this trial is allowed provided patient is eligible (see
section6.9.2).
For patients with MPP, concurrent therapy with somatostatin, and
somatostatin analogues is allowed provided tumor progression on this
therapy has been demonstrated; concurrent therapy with
bisphosphonates (e.g. zoledronic acid) or denosumab is also allowed.
5. Patients with an initial diagnosis of ACC less than 9 months from start
of screening part 2.
6. Patients with ACC and any individual lesion according to RECIST 1.1
having a maximum diameter of more than 125 mm; irrespective if the
lesion is proposed as a target lesion, or not, according to RECIST 1.1.
7. Patients with ACC with more than three organs involved by disease.
8. Patients with ACC and uncontrolled hormonal secretion (according to
the judgement of the treating physician).
9. Patients with MPP and uncontrolled blood pressure (according to the
judgement of the treating physician).
10. Patients with abnormal laboratory values according to the following
list :
a. lymphocyte count decreased, grade 2 (lymphocytes <800 - 500/mm3;
<0.8 - 0.5 x 109/L), or worse grade,
b. hemoglobin < 8 g/dL (9 mmol/L) i.e. anemia Grade 2 is acceptable if
judged by the Investigator as not constituting a safety risk in the
individual patient,
c. white blood cell count decrease (< 3.0 × 109/L),
d. absolute neutrophil count decrease (< 1.5 × 109/L),
e. platelet count decrease (< 75 × 109/L),
f. total bilirubin > 1.5 x upper limit of normal (ULN)
g. alanine aminotransferase (ALT) > 3 x ULN; if disease metastatic to the
liver > 5 x ULN,
h. aspartate aminotransferase (AST) > 3 x ULN; if disease metastatic to
the liver > 5 x ULN,
i. serum creatinine increase (> 1.5 x ULN); however, if creatinine
clearance (measured, or calculated according to the Cockcroft/Gault or
the CKD-EPI equation) is > 40 mL/minute the patient can be enrolled,
j. abnormal thyroid function per local laboratory levels (note, patients
with hypothyroidism only requiring hormone replacement therapy are
permitted to enroll, also patients with abnormal laboratory values
judged by the treating physician as clinically non-relevant and related to
mitotane treatment are allowed to enroll).
11. Patients with persistent Grade 3 or 4 toxicities (according to
NCICTCAE v5.0) after prior treatments; toxicities must be resolved since
at least 2 weeks before study treatment start to Grade 1 or less.
However, alopecia or other persisting toxicities Grade ≤ 2 not
constituting a safety risk based on Investigator's judgment are
acceptable.
12. Uncontrolled central nervous system (CNS) metastasis; patients with
history of CNS metastases are eligible if CNS disease has been
radiographically and neurologically stable for at least 6 weeks prior to
ICF signing and do not require corticosteroids (of any dose; for the CNS
disease specifically) for symptomatic management.
13. Other malignancy or prior malignancy with a disease-free interval of
less than 3 years prior to ICF signing; except those treated with surgical
intervention and an expected low likelihood of recurrence such as basal
cell or squamous cell skin cancer, or carcinoma in situ, i.e. patients with
adequately treated basal cell or squamous cell skin cancer, or carcinoma |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- The primary endpoint of the phase 1 part includes safety and
tolerability of EO2401 in combination with nivolumab is a descriptive
medical assessment of the combined profile of incidences of adverse
events (AEs), treatment-emergent AEs (TEAEs), serious AEs (SAEs),
deaths, reasons for treatment discontinuation/delays, and laboratory
abnormalities using the NCI-CTCAE v5.0 grading system.
- The primary endpoint of the phase 2 part is the rate of patients without
progression (according to iRECIST criteria [37]) or death due to any
cause at 6 months after the first dose of randomized treatment. Six
months after the first dose of randomized treatment will be determined
for each patient and is dependent on the exact time point of evaluation
of the CT investigation scheduled at week 25 (day 169). The primary
endpoint is to be determined per investigator/local site assessments of
progression. The denominator will be all patients who started the
randomized treatment in Cohort 2A* and will be determined for each
randomized treatment group separately. Patients will be followed up for
progression or death during the first 6 months after start of randomized
treatment regardless of whether they stop treatment and continue on
other regimens. Patients who are completely lost to follow-up will be
counted as if they had a PFS event during the first 6 months.
* Cohort 2A = patients with ACC who had prior systemic therapy for
established locally advanced or metastatic disease |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
AEs will be monitored throughout the study. AEs are collected from the date of the patient's signing the ICF until 30 days after the final administration of study drug. SAEs with a plausible causal relationship to study drug will be reported from the date of the patient's signing the ICF until indefinitely (regardless of time elapse from the final study drug administration). An AE causally not related to study drug will be monitored (followed-up) until resolution, stabilization, or end of the clinical trial. Clinically relevant laboratory abnormalities will be followed up until they return to normal or become stabilized (permanent condition). Any AE with a plausible causal relationship to study drug as well as all SAEs will be followed up until the event has resolved or
stabilized. |
|
| E.5.2 | Secondary end point(s) |
The key secondary endpoints of the trial are:
• Percentage of patients with shown immunogenicity (expansion of
specific T cells comparing samples taken at baseline versus on treatment
in an individual patient determining if the patient has a positive response
to the immunization, or not) in relation to EO2316, EO2317, EO2318, and
UCP2 that compose EO2401 by interferon-gamma (IFN-γ) enzyme-linked
immunospot (ELISpot), and by intracellular cytokines staining, or
multimers staining assays. Cross reactivities with the human TAAs
IL13Rα2, FOXM1, and BIRC5/survivin will also be evaluated by the same
methods.
The other secondary endpoints of the trial are:
• ORR, time to response and DOR as described by RECIST 1.1 and
iRECIST criteria.
• PFS as described by RECIST 1.1 and iRECIST criteria, defined as the
time interval from the date of first study treatment administration to the
date of progression (by RECIST 1.1 or iRECIST criteria) or death due to
any cause, whichever is earlier. Patients without progression or death
are to be censored at the time of the last tumor assessment.
• OS defined as the time interval from the date of first study treatment
administration to the date of death due to any cause. Patients alive will
be censored at the date of the last documented follow-up.
• In addition, in the randomized extension of Cohort 2A safety and
tolerability of EO2401/nivolumab will be assessed versus internal
concurrent controls (groups of patients treated with EO2401
monotherapy and nivolumab monotherapy, respectively), by incidences
of adverse events (AEs), treatment-emergent AEs (TEAEs), serious AEs
(SAEs); AEs will be analyzed irrespective of relationship, and as related
events. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Percentage of patients with shown immunogenicity is evaluated on
Week 1, 5 , 7 , 11, 15 and 19, then every 4 weeks of treatment onwards.
Post treatment is evaluated on Day 30 and every 8 weeks before disease
progression
• Objective Response Rate (ORR) and Duration of Response (DOR) as
described by RECIST 1.1 and iRECIST criteria
• PFS as described by RECIST 1.1 and iRECIST criteria, defined as the
time interval from the date of first study treatment administration to the
date of progression (by RECIST 1.1 or iRECIST criteria) or death due to
any cause, whichever is earlier. Patients without progression or death
are to be censored at the time of the last tumor assessment. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| A phase Ib/II trial but another trial is the Fist in Human |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| The trial is a 5-cohort study |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
| Sweden |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last Visit Last Patient (LVLP) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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