Dose-finding:-To determine the adult equivalent exposure/MTD/recommended Phase II pediatric dose of durvalumab monotherapy and durvalumab in combination with tremelimumab-To determine the safety profile of durvalumab monotherapy, or durvalumab in…
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Source
Brief title
Condition
- Other condition
Synonym
Health condition
Advanced Solid Tumors and Hematological Malignancies
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Dose-finding:
1. Based on PK parameters (including Cmax, Cmin, AUC, and others), identify the
adult equivalent exposure/MTD of durvalumab monotherapy and durvalumab in
combination with tremelimumab among children and young adults from birth to <18
years of age with advanced solid tumors and non-Hodgkin lymphoma, using a q4w
dosing schedule.
2. Identify the safety and tolerability of durvalumab monotherapy and
durvalumab in combination with tremelimumab at the adult equivalent
exposure/MTD among children and young adults from birth to <18 years of age
with advanced solid tumors and non-Hodgkin lymphoma, using a q4w dosing
schedule. Endpoints include AEs, vital signs, physical examinations, ECGs, and
laboratory evaluations.
Dose-expansion:
3. Objective response rate as determined by the Investigator assessed RECIST
1.1 or alternative pre-specified tumor-specific response rates for different
scoring systems.
-Assessment of antitumor activity will be specific to tumor cohort, eg,
Investigator assessed RECIST 1.1 and Cheson criteria (other malignancies will
be analyzed based on the best response assessed by the Investigator).
4. Additional efficacy endpoints that will be collected include DoR, BoR, DCR,
PFS, APF12, and APF18 based on RECIST 1.1, Cheson criteria, Wayne criteria, or
INRC assessed by the Investigator, and OS, OS12, and OS24 as appropriate to
each individual cohort.
Secondary outcome
5. Individual durvalumab and tremelimumab concentrations in serum, and PK
parameters including Cmax, Cmin, AUC.
6. Number and percentage of patients who develop detectable ADAs.
7. Individual antibody titer measurements before and after planned routine
immunization during treatment and Cycle 4 or follow-up, whichever is earlier.
8. Flow cytometry for CD4, CD8, B and NK cells, including T-cell activation
with Ki67
Background summary
Standard therapy for solid and hematological pediatric tumors includes various
combinations of surgery, cytotoxic chemotherapy, and radiation. These
treatments can have detrimental consequences to a developing child, and many
survivors carry a substantial burden of long-term
morbidities. With improved survival rates, children with cancer are likely to
live longer, with the risk of long-term toxicity being an important crucial
factor. In addition, there is an overall unmet medical need for more effective
therapies for pediatric patients who have relapsed/refractory
disease. Attractive alternatives would include biological agents that do not
include toxic chemotherapy and target alternative carcinogenesis pathways that
may have acquired resistance from the previous therapies. Immune checkpoint
inhibitors may be such candidates, with
promising and positive outcomes in adults with melanoma, lung cancer, bladder
cancer, gastric cancer, microsatellite instability in colorectal cancer, and
other malignancies.
Study objective
Dose-finding:
-To determine the adult equivalent exposure/MTD/recommended Phase II pediatric
dose of durvalumab monotherapy and durvalumab in combination with tremelimumab
-To determine the safety profile of durvalumab monotherapy, or durvalumab in
combination with tremelimumab.
Dose-expansion:
To determine the preliminary antitumor activity of durvalumab monotherapy and
durvalumab in combination with tremelimumab at the recommended dose, using
cohort-specific response criteria (eg, Cheson criteria and RECIST 1.1).
Study design
Open-label, non-randomized, international, multicenter study investigating
durvalumab in combination with tremelimumab (q4w for 4 cycles only) followed by
durvalumab monotherapy (q4w) in pediatric patients from birth to <18 years of
age with relapsed or refractory malignant solid tumors and hematological
malignancies. Durvalumab in combination with tremelimumab will be examined in
all solid malignant tumors (except primary central nervous system tumors) and
hematological malignancies (with the exception of patients with Hodgkin
lymphoma [HL], who will receive treatment with durvalumab only).
The study will be conducted in 2 sequential phases: a dose-finding phase,
followed by a dose-expansion phase.
Intervention
Durvalumab + tremelimumab combination therapy (dose-finding phase):
• Durvalumab monotherapy q4w will be given via intravenous (IV) infusion at
Cycle 1.
Patients will receive durvalumab in combination with tremelimumab via IV
infusion q4w, starting on Cycle 2, for up to a maximum of 4 doses/cycles. Four
weeks after the last infusion of the combination, durvalumab monotherapy via IV
infusion q4w may be given until clinical or confirmed PD, or other
discontinuation criteria is met, whichever comes first.
Durvalumab + tremelimumab combination therapy (dose-expansion phase):
• Durvalumab in combination with tremelimumab via IV infusion q4w will be given
for up to a maximum of 4 doses/cycles. Four weeks after the last infusion of
the combination, durvalumab monotherapy via IV infusion q4w may be given until
clinical or confirmed PD, or other discontinuation criteria is met, whichever
comes first.
Durvalumab monotherapy (patients with HL in dose-expansion phase only):
• Durvalumab monotherapy via IV infusion q4w will be given in patients with HL
until clinical or confirmed PD, or other discontinuation criteria is met,
whichever comes first. Patients will be eligible to receive tremelimumab if
they progress on durvalumab monotherapy.
Study burden and risks
Monoclonal antibodies directed against immune checkpoint proteins, such as
PD-L1 as well as those directed against PD-1 or CTLA-4, aim to boost endogenous
immune responses directed against tumor cells. By stimulating the immune
system, however, there is the potential for
adverse effects on normal tissues.
Most adverse drug reactions seen with the immune checkpoint inhibitor class of
agents in adults are thought to be due to the effects of inflammatory cells on
specific tissues. These risks are generally events with a potential
inflammatory or immune-mediated mechanism and that may require more frequent
monitoring and/or unique interventions such as immunosuppressants and/or
endocrine therapy. These immune-mediated effects can occur in nearly any organ
system, and are most commonly seen as gastrointestinal (GI) AEs such as colitis
and diarrhea,
pneumonitis/interstitial lung disease (ILD), hepatic AEs such as liver enzyme
elevations, skin events such as rash and dermatitis, and endocrinopathies
including hypo- and hyper-thyroidism. It is still too early to describe the
specific toxicity profiles for durvalumab monotherapy and
durvalumab in combination with tremelimumab in pediatric patients. However,
data from other immune checkpoint inhibitors and limited data from study
D419C00028 (ongoing study evaluating durvalumab monotherapy in pediatrics) has
shown safety profiles in pediatric patients
consistent with those observed in adults.
The safety profile of durvalumab and durvalumab in combination with
tremelimumab is expected to follow the same pattern as other immune checkpoint
inhibitors in regards to imAEs.
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Listed location countries
Age
Inclusion criteria
• Patients must have pathologically confirmed relapsed or refractory advanced
solid tumour malignancy or haematological malignancies including lymphoma and
acute leukaemia. Any number of prior treatment regimens allowed. A select group
of first-line patients may be eligible for screening and enrolment. These
patients will be enrolled based on investigator assessment as patients for whom
no curative standard of care treatment options exist or such therapies are not
tolerable.
• If available, patients must provide a diagnostic tumor sample taken *3 years
prior to screening for evaluation of PD-L1 status.
• Lansky play performance scale >=50 for patients >=1 and <16 years of age and
Karnofsky performance status score >=50 for patients >=16 years of age (patients
<1 year of age are exempt from this criterion)
• Patients must have measurable/evaluable disease as defined by methods used in
common clinical practice.
• No prior exposure to immune checkpoint inhibitors or genetically engineered
cellular therapies including, but not limited to, other anti- CTLA-4,
anti-PD-1, anti-PD-L1, anti-PD-L2 antibodies and antibodies of CAR-T or other
cell therapies, excluding therapeutic anticancer vaccines.
Exposure to other investigational agents may be permitted after discussion with
the Sponsor or designee.
Exclusion criteria
• History of allogeneic organ transplantation (exceptions may be allowed for
HL, NHL, ALL and AML, after discussion with Sponsor or designee). Patients who
have previously received an autologous bone marrow transplant may be eligible
• Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease, diverticulitis, celiac disease or other serious GI
chronic conditions associated with diarrhea, systemic lupus erythematosus,
Wegener syndrome; myasthenia gravis, Graves' disease, rheumatoid arthritis,
hypophysitis, uveitis, etc) autoimmune myocarditis, and autoimmune pneumonitis.
The following are exceptions to this criterion:
* Patients with vitiligo or alopecia
* Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on
hormone replacement
* Psoriasis that does not require systemic therapy
* Patients with celiac disease controlled by diet alone.
• Uncontrolled intercurrent illness, including but not limited to, ongoing or
active infection, symptomatic congestive heart failure, cardiac arrhythmia,
ILD, or psychiatric illness or social situations that would
limit compliance with study requirements, substantially increase risk of
incurring AEs from IP, or compromise the ability of the patient to give written
informed consent.
• History of primary immunodeficiency.
• Active infection including tuberculosis, hepatitis B, hepatitis C, or HIV.
Patients with a past or resolved HBV infection are eligible. Patients positive
for hepatitis C virus (HCV) antibody are eligible only if polymerase chain
reaction is negative for HCV ribonucleic acid (RNA).
• Any unresolved toxicity NCI CTCAE version 5.0 Grade >=2 from previous
anticancer therapy with the exception of alopecia, vitiligo, lymphopenia and
the laboratory values defined in the inclusion criteria
* Patients with Grade >=2 neuropathy will be evaluated on a case-bycase basis
and may be included after consultation with the Study Physician.
* Patients with toxicity not reasonably expected to be exacerbated by treatment
with durvalumab or tremelimumab (eg, hearing loss, gastrostomy tube) may be
included after consultation with the Study
Physician.
• Patients with clinically active brain metastases (known or suspected) or
spinal cord compression, and choloromas are excluded, unless these conditions
have been previously treated and are considered stable.
• History of leptomeningeal carcinomatosis, or involvement of any other
anatomic area that, in the opinion of the Investigator, may cause significant
symptoms if an inflammatory reaction occurs.
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 | EUCTR2018-003118-42-NL |
| CCMO | NL67429.041.19 |