The objective of this trial is to evaluate safety and tolerability of an experimental drug, EO2401, in combination with another immunological treatment, nivolumab, in patients with advanced or metastatic ACC and progressive MPP.
ID
Source
Brief title
Condition
- Adrenal gland disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of the phase 1 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
Secondary outcome
The key secondary endpoints of the trial are:
• Percentage of patients with shown immunogenicity in relation to EO2316,
EO2317, EO2318, and UCP2 that compose EO2401
The other secondary endpoints of the trial are:
• Objective response rate, time to response and Duration of response as
described by RECIST 1.1 and iRECIST criteria.
• Progression-free survival 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.
• Overall survival 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 assessed versus internal concurrent controls
Background summary
Two different primary malignancies can arise from the adrenal gland:
adrenocortical carcinoma (ACC) from the adrenal cortex and malignant
pheochromocytoma from the adrenal medulla.
ACC has an estimated incidence of *0.7-2 new cases per million people per year.
The incidence of pheochromocytoma/paraganglioma is *2-8 per million adults per
year. Approximately 10% - 15% of pheochromocytomas and paragangliomas are
malignant.
The two primary malignancies arising from the adrenal glan, are tumors with
quite different characteristics from many biological perspectives. However,
from a general treatment perspective they show similarities:
• Surgery is of utmost importance, and the only curative treatment modality,
provided radical surgery can be performed.
• Treatment options for patients with unresectable disease are few and new
treatment options have not been added recently.
• The currently available first line therapies in both entities are only
achieving tumor regression in approximately one in four patients at the cost of
a relatively high toxicity burden
• Even though the median survival in patients with MPP (approx. 6-7 years) is
longer than for patients with ACC (around 12-15 months), half of the patients
with MPP have progressive disease within one year and require active
management. Thus, it seems fair to conclude that for both entities there are
unmet medical needs with respect to new efficacious systemic therapies.
Novel therapeutic approaches are needed to enhance the treatment outcomes for
patients with adrenal malignancies.
Study objective
The objective of this trial is to evaluate safety and tolerability of an
experimental drug, EO2401, in combination with another immunological treatment,
nivolumab, in patients with advanced or metastatic ACC and progressive MPP.
Study design
This is an open-label, 3-cohort study. The patients will be allocated in one of
the 5 cohorts (group) of the study :
• Cohort 1 : will include previously treated patients. The patients will
receive a subcutaneous injection of 1 ml of EO2401 every 2 weeks during the
priming phase (8 weeks) and every 4 weeks during the boosting phase, in
combination with nivolumab at standard dose; patients with ACC and MPP will be
included. Three to 12 evaluable patients will be included depending on the
safety profile of the administered treatments. The aim of this cohort is to
find the adequate dose of EO2401.
• Cohorts 2A (previously treated patients) and 2B (previously untreated
patients) includes an evaluation of EO2401 at the recommended dose found in
Cohort 1 in combination with nivolumab in 30 evaluable patients (15 each for
Cohorts 2A and 2B) with ACC. The patients will receive a subcutaneous injection
of 1 ml of EO2401 every 2 weeks during the priming phase (8 weeks) and every 4
weeks during the boosting phase. In addition, through Protocol v3.0, there is a
randomized extension of cohort 2A in 3 sub-groups: 43 patients in Cohort 2A-I
(EO2401 and nivolumab), 11 patients in Cohort 2A-II (EO2401 monotherapy) and 11
patients in Cohort 2A-III (nivolumab monotherapy).
• Cohorts 3A (previously treated patients) and 3B (previously untreated
patients) includes an evaluation of EO2401 at the recommended dose found in
Cohort 1 in combination with nivolumab in 20 evaluable patients (no specific
split between Cohorts 3A and 3B) with progressive MPP. The patients will
receive a subcutaneous injection of 1 ml of EO2401 every 2 weeks during the
priming phase (8 weeks) and every 4 weeks during the boosting phase.
Treatment will continue until either the disease worsens, the patient
experiences intolerable study drug effects or the sponsor terminates this
study.
Intervention
Cohort 1
Priming Phase
Injection of 1 ml of EO2401 every 2 weeks. EO2401 injections will be given 4
times in total during this phase. An intravenous infusion of nivolumab will be
given 3 hours after treatment with EO2401. The dose of nivolumab should be 240
mg every 2 weeks for the first 3 administrations and at the dose of 480 mg on
the 4th administration and onwards .
Boosting Phase
Injection of 1 ml of EO2401 every 4 weeks, in combination with an intravenous
infusion of nivolumab every 4 weeks at the dosage of 480mg.
Cohorts 2 or Cohorts 3 if the EO2401 is well tolerated in Cohort 1 as follows:
Priming Phase
Injection of 1 ml of EO2401, in combination with an intravenous infusion of
nivolumab every 2 weeks. The EO2401 injection in combination with the nivolumab
infusion every 2 weeks will be given 4 times in total. The dose of nivolumab
should be 240 mg every 2 weeks for the first 3 administrations and at the dose
of 480 mg on the 4th administration and onwards.
Boosting Phase
After completing the Priming Phase, 1 subcutaneous injection of EO2401 every 4
weeks, in combination with an intravenous infusion of nivolumab every 4 weeks
at the dosage of 480mg.
When EO2401 and nivolumab are administered as monotherapy (Cohorts 2A-II and
2A-III), their respective schedules of administration are the same as in
combination treatment.
Study burden and risks
The risks associated with the study and study procedures are :
Blood sample collection: It may be painful when blood is drawn . Some people
get dizzy or faint from a blood draw. The patient could also get an infection,
which is rare, or have bleeding, redness, or bruising at the skin puncture.
Central venous catheters (port-a-catheter): In addition to the risks described
above for blood sample collection, a port-a-catheter may cause bloodstream
infection and embolism.
Nivolumab: Infusion-related reactions may occur, in rare cases with fatal
outcome. These infusion-related reactions may include symptoms of allergic
reactions, such as tightening of the muscles in the lungs, bronchospasm, skin
rash, increase or decrease in blood pressure, loss of consciousness or shock.
In rare cases, chest pain or discomfort, heart attack or sudden loss of heart
function may happen.
Montanide : the most common side effects related to an injection of montanide
are local reactions such as local pain, tenderness, redness and granuloma at
the injection site. The intensity is usually mild to moderate . The exact
frequency of all these reactions is not known.
Other general reactions are mainly flu-like symptoms such as fatigue, chills,
fever and headaches. Lack of energy and nausea were also observed. The
intensity was usually mild or moderate. Upon subsequent vaccination using a
different limb, some earlier injection sites developed new inflammatory signs,
showing that they were reactivated.
EO2401: Side effects related to the administration of EO2401 may be local pain
or redness or induration or even ulceration at the injection site.
These local administration site reactions could be observed in up to 54% of
patients. These reactions might start a few weeks after administration, could
last several weeks or months, and are usually mild to moderate, severe being
uncommon.
ECGs: minor skin irritation may occur at the locations where the electrodes are
placed.
CT scan: the most common CT scan side effects are:
• Potential allergic reactions to the contrast material if this material is
used.
• Potential feeling of being anxious because of the uncertainty of the
diagnosis and possibly scared because of the enclosed space.
• Potential increased risk of cancer which is a known medical risk after
increased exposure to radiation and scans
Avenue Ledru-Rollin 94/96
Paris 75011
FR
Avenue Ledru-Rollin 94/96
Paris 75011
FR
Listed location countries
Age
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 responses to
local therapy (e.g. resection) 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 18-months 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.
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 include:
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; the first minimized consent
related to the procedure of HLA-testing, and the second to all other trial
details and procedures.
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 trail
is allowed provided patient is eligible (see section 6.9.2). 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, combined
with unresectable primary tumor.
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
(note, lab ranges according to the performing laboratory's reference ranges):
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, and
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 NCI-CTCAE
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 in situ are
eligible.
14. Patients with clinically significant active infection, cardiac disease,
significant medical or psychiatric disease/condition that, in the opinion of
the Investigator, would interfere with the evaluation of study results,
interpretation of patient safety, or prohibit patient understanding of the
informed consent procedure (i.e. only consent able patients can be enrolled in
the study) or compliance with the requirements of the protocol - including (but
not limited to):
a. bacterial sepsis or similarly severe infections,
b. uncontrolled or significant cardiovascular disease, including:
i. New York Heart Association > Grade 2 congestive heart failure within 6
months prior to ICF signing,
ii. myocardial infarction within 6 months prior to ICF signing,
iii. uncontrolled/unstable angina within 6 months prior to ICF signing,
iv. diagnosed or suspected congenital long QT syndrome,
v. any history of clinically significant ventricular arrhythmias (such as
ventricular tachycardia, ventricular fibrillation, or Torsades de pointes),
c. stroke within 6 months prior to ICF signing,
d. concurrent neurodegenerative disease, and
e. dementia or significantly altered mental status.
15. Patients with suspected autoimmune or active autoimmune disorder or known
history of an autoimmune neurologic condition (e.g. Guillain-Barré syndrome).
Note, patients with vitiligo, type I diabetes mellitus, hypothyroidism due to
autoimmune condition only requiring hormone replacement therapy, psoriasis not
requiring systemic therapy, or conditions not expected to recur in the absence
of an external trigger are permitted to enroll.
16. Patients with history of solid organ transplantation or hematopoietic stem
cell transplantation.
17. Patients with history or known presence of tuberculosis.
18. Pregnant and breastfeeding patients.
19. Patients with history or presence of human immunodeficiency virus and/or
potentially active hepatitis B virus/hepatitis C virus infection.
20. Patients who have received live or attenuated vaccine therapy used for
prevention of infectious diseases including seasonal (influenza) vaccinations
within 4 weeks of the first dose of study drug.
21. Patients with a history of hypersensitivity to any excipient present in the
pharmaceutical forms of the study treatments.
22. Patients treated with herbal remedies with immunostimulating properties or
known to potentially interfere with major organ function.
23. Patients with known ongoing drug and alcohol abuse.
24. Patients with known or underlying medical or psychiatric condition that, in
the Investigator*s opinion, would make the administration of study drug
hazardous to the patient or obscure the interpretation of toxicity
determination or AEs.
25. Patients deprived of their liberty, under protective custody, or guardship.
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 | EUCTR2019-003396-19-NL |
| ClinicalTrials.gov | NCT04187404 |
| CCMO | NL71766.000.19 |