Trial Title:
Study of the Efficacy of Intratumoral L19IL2 or L19TNF or L19IL2/L19TNF, in Combination with Pembrolizumab, in Unresectable Melanoma Patients
NCT ID:
NCT06284590
Condition:
Melanoma Stage III
Melanoma Stage IV
Conditions: Official terms:
Melanoma
Pembrolizumab
Interleukin-2
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Intervention model description:
162 patients. Patients enrolled will be randomized in a 1:1:1 ratio. i) systemic
pembrolizumab in combination with intralesional L19IL2 (Arm 1): 54 patients.
ii) systemic pembrolizumab in combination with intralesional L19TNF (Arm 2): 54 patients
iii) systemic pembrolizumab in combination with intralesional L19IL2/L19TNF (Arm 3): 54
patients
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
L19IL2
Description:
Arm 1: The amount of L19IL2 that is intratumorally administered into injectable
cutaneous, subcutaneous, and nodal tumors once weekly for up to 4 weeks is dependent on
the size of the tumor. The maximum dose to be administered in a single treatment visit is
13 MioIU/1 mL of L19IL2.
Arm group label:
Systemic pembrolizumab in combination with intralesional L19IL2 (Arm 1)
Other name:
bifikafusp alfa
Intervention type:
Drug
Intervention name:
L19TNF
Description:
Arm 2: The amount of L19TNF that is intratumorally administered into injectable
cutaneous, subcutaneous, and nodal tumors once weekly for up to 4 weeks is dependent on
the size of the tumor. The maximum dose to be administered in a single treatment visit is
400 μg/1 mL of L19TNF.
Arm group label:
Systemic pembrolizumab in combination with intralesional L19TNF (Arm 2)
Other name:
onfekafusp alfa
Intervention type:
Drug
Intervention name:
L19IL2/L19TNF
Description:
Arm 3: The amount of L19IL2/L19TNF that is intratumorally administered into injectable
cutaneous, subcutaneous, and nodal tumors once weekly for up to 4 weeks is dependent on
the size of the tumor. The maximum dose to be administered in a single treatment visit is
13MioIU L19IL2 + 400 μg L19TNF in a combined total volume of approximate 2 mL. In case
that study drug-related, grade ≥ γ AEs are recorded after the first L19IL2/L19TNF dose
administration, the L19TNF dose is reduced to 200 μg for the following administrations.
Arm group label:
Systemic pembrolizumab in combination with intralesional L19IL2/L19TNF (Arm 3)
Other name:
Daromun
Intervention type:
Drug
Intervention name:
KEYTRUDA®
Description:
KEYTRUDA® will be administered by i.v. infusion as a dose of 200 mg on the first day of
intralesional treatment with ICKs and will continue every 3 weeks for approximately 2
years, 35 cycles, 2 year cap or until disease progression or unacceptable toxicity,
whichever comes first. ICKs intralesional treatment will be administered 30-60 minutes
post administration of KEYTRUDA®.
Arm group label:
Systemic pembrolizumab in combination with intralesional L19IL2 (Arm 1)
Arm group label:
Systemic pembrolizumab in combination with intralesional L19IL2/L19TNF (Arm 3)
Arm group label:
Systemic pembrolizumab in combination with intralesional L19TNF (Arm 2)
Other name:
pembrolizumab
Summary:
The trial aims to evaluate the efficacy of single agent L19IL2, single agent L19TNF, and
combination L19IL2+L19TNF given concurrently with anti-PD1 therapy compared to historical
control of anti-PD-1 re-challenge alone for anti-PD1 refractory unresectable stage III-IV
melanoma.
Detailed description:
The present study is a randomized, open-label, three-arm, parallel phase 2 study. A Simon
two-stage design for the study of the efficacy of intralesional therapy with L19IL2 or
L19TNF or L19IL2/L19TNF in combination with systemic anti-PD1 pembrolizumab immunotherapy
will be used.
In the study, 162 patients will be randomized in a 1:1:1 ratio to receive:
i) systemic pembrolizumab in combination with intralesional L19IL2 (Arm 1) or ii)
systemic pembrolizumab in combination with intralesional L19TNF (Arm 2) or iii) systemic
pembrolizumab in combination with intralesional L19IL2/L19TNF (Arm 3).
This is an open-label study, so there is no blinding.
The study consists of a two-week screening period, followed by a 4-weeks open-label
intralesional treatment period with immunocytokines (ICKs) either L19IL2, L19TNF or
L19IL2/L19TNF. Pembrolizumab will be administered by i.v. infusion on the first day of
intralesional treatment with ICKs, and will continue every 3 weeks for approximately 2
years, 35 cycles, 2 year cap or until disease progression or unacceptable toxicity,
whichever comes first.
Follow-up for progression free survival will be performed up to 2 years after first
intralesional treatment. Survival information will be collected up to 3 years after first
intralesional treatment.
A safety run-in will be performed on the first 12 patients enrolled in each arm of the
study. Patients will be evaluated during the first 21-days cycle for the occurrence of
the treatment-related adverse events. All toxicities will be graded using NCI CTCAE
Version 5.0 based on the investigator assessment to be possibly, probably, or definitely
related to study treatment administration.
In addition to this, safety information collected will be routinely reviewed by the Data
and Safety Monitoring Board (DSMB) in order to identify possible safety concerns.
The primary objective of the study is to demonstrate the efficacy of intralesional
treatment with ICKs, in combination with systemic anti-PD1 immunotherapy with
pembrolizumab, to induce objective responses in advanced melanoma patients with
resistance to or progressing upon anti-PD1 checkpoint inhibitors.
Primary endpoint of the study is the Confirmed Objective Response Rate (ORR = CR + PR) in
all three arms over a period of up to 2 years after first intralesional treatment,
according to RECIST v1.1 criteria in each arm of the study. The primary analysis will be
performed in the Intention-to-Treat population (ITT).
For each of the three treatment arms, secondary objectives include efficacy and safety of
intralesional treatment with ICKs.
The secondary endpoints include:
- Best overall response (BOR; the best overall response is the best response recorded
from the start of the treatment until disease progression/recurrence according to
RECIST v1.1 criteria)
- Duration of response (DoR)
- Pathological response of one target lesion injected with ICKs at 18 weeks after
first treatment
- Confirmed ORR over a period of up to 2 years after first intralesional treatment,
according to iRECIST (see Appendix 1) and itRECIST [1] criteria in each arm of the
study
- Progression-free survival (PFS) from time of randomization
- Overall survival (OS) from randomization
- Number, frequency and grading of adverse events (AEs) and serious adverse events
(SAEs) related to intralesional therapy with ICKs in combination with systemic
anti-PD1 therapy
End of treatment: last day of anti-PD1 therapy or until progression or unacceptable
toxicity.
End of study: corresponds to the last patient last visit (LPLV).
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. The participant (or legally acceptable representative if applicable) provides
written informed consent for the trial.
2. Be > or equal to 18 years of age on day of signing informed consent.
3. Participant with histologically or cytologically confirmed diagnosis of unresectable
metastatic melanoma at stage III B, C, D or IV M1a (AJCC 8th ed.). Patients with
Stage IVM1b, M1c and M1d oligometastatic disease [up to 10 lesions in aggregate
including lung, liver, bone or brain, with or without lymph node involvement], are
eligible. However, patients with symptomatic or rapidly enlarging/bleeding brain
lesions are excluded. Patients with acral lentiginous melanoma are eligible as well.
Detailed information about prior therapies and burden of disease at study entry must
be available.
4. Patients must have confirmed primary resistance to or acquired resistance on
treatment with an anti-PD1/L1 monoclonal antibody (mAb) administered either as
monotherapy, or in combination with other checkpoint inhibitors or other therapies.
PD-1 treatment progression is defined by meeting all of the following criteria: a.)
Has received at least 2 doses of an approved anti-PD-1/L1 mAb.
b.) Has demonstrated disease progression (PD) after PD-1/L1 as defined by RECIST
v1.1. The initial evidence of PD is to be confirmed by a second assessment no less
than four weeks from the date of the first documented PD, in the absence of rapid
clinical progression. c.) Progressive disease has been documented within 12 weeks
from the last dose of anti- PD-1/L1 mAb.
i. Progressive disease is determined according to iRECIST. ii. This determination is
made by the investigator. Once PD is confirmed, the initial date of PD documentation
will be considered the date of disease progression.
5. Patients harboring the BRAF mutation who received BRAF/MEK inhibition (or declined
BRAF/MEK inhibitors) and received thereafter anti-PD1 therapy showing resistance to
such immunotherapy are eligible to the study. Anti-PD1 immunotherapy must be the
last therapy received by the patient prior to randomization.
6. Eligible subjects must have measurable disease (according to RECIST v1.1) as
assessed by the local site investigator/radiology. Lesions situated in a previously
irradiated area are considered measurable if progression has been demonstrated in
such lesions. Eligible subjects must be a candidate for intralesional therapy with
at least one injectable cutaneous, subcutaneous, or nodal metastatic melanoma lesion
(≥ 5 mm in longest diameter) or with multiple injectable lesions that in aggregate
have a diameter of ≥ 5 mm.
7. A female participant is eligible to participate if she is not pregnant, not
breastfeeding, and at least one of the following conditions applies: a.) Not a woman
of childbearing potential (WOCBP) b.) A WOCBP who agrees to follow contraceptive
guidance during the treatment period and for at least 120 days after the last dose
of study treatment. WOCBP must be using for the time period indicated highly
effective contraception methods. WOCBP and effective contraception methods are
defined by the "Recommendations for contraception and pregnancy testing in clinical
trials" issued by the Head of Medicine Agencies' Clinical Trial Facilitation Group
and which include, for instance, progesterone-only or combined (estrogen- and
progesterone-containing) hormonal contraception associated with inhibition of
ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral
tubal occlusion, vasectomized partner or sexual abstinence. Pregnancy test will be
repeated at the safety visit (only WOCBP).
8. Have provided archival tumor tissue sample or newly obtained core or excisional
biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin
embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are
preferred to archived tissue.
Note: If submitting unstained cut slides, newly cut slides should be submitted to
the testing laboratory within 14 days from the date slides are cut (details
pertaining to tumor tissue submission can be found in the Procedures Manual).
9. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
10. Have adequate organ function as defined in the following table. Specimens must be
collected within 14 days prior to the start of study treatment.
11. Be able to provide a core or excisional lymph node biopsy for biomarker analysis
from an archival or newly obtained biopsy at Screening. In addition, participants
may provide additional biopsy at Week 18 and at the time of discontinuation due to
progression
12. Documented negative test for HIV, HBV and HCV. For HBV serology, the determination
of HBsAg and anti-HBcAg Ab is required. In patients with serology documenting
previous exposure to HBV (e.g. anti-HBsAg and/or anti-HBc Ab) a negative serum
HBV-DNA test is also required.
13. All acute toxic effects (excluding alopecia and vitiligo) of any prior therapy must
have resolved to National Cancer Institute (NCI) Common Terminology Criteria for
Adverse Events (CTCAE) (v. 5.0) Grade ≤ 1 or baseline unless otherwise specified
above. Note: Participants with ≤Grade β neuropathy may be eligible. Participants
with endocrinerelated AEs Grade ≤β requiring treatment or hormone replacement may be
eligible. Note: If the participant had major surgery, the participant must have
recovered adequately from the procedure and/or any complications from the surgery
prior to starting study intervention.
14. Full resolution of checkpoint blockade therapy-related adverse effects (including
immunerelated adverse effects) and no treatment for these AEs for at least 4 weeks
prior to the time of enrollment.
15. No history of severe immune related adverse effects from prior given immune
checkpoint blockade therapy (CTCAE Grade 4; CTCAE Grade 3 requiring treatment >4
weeks).
16. Male patients with WOCBP partners must agree to use simultaneously two acceptable
methods of contraception (i.e. spermicidal gel plus condom) from the screening to
three months following the last study drug administration. In addition, male
participant must refrain from sperm donation during the treatment period.
17. Willingness and ability to comply with the scheduled visits, treatment plan,
laboratory tests and other study procedures.
Exclusion Criteria:
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Patients with more than 10 distant melanoma lesions in lung, liver, bone or brain
combined. Patients with symptomatic or rapidly enlarging/bleeding brain lesions are
excluded.
2. Uveal melanoma or mucosal melanoma or melanoma with unknown primary.
Pregnancy Exclusion
3. A WOCBP who has a positive urine pregnancy test (within 72 hours) prior to
treatment. If the urine test is positive or cannot be confirmed as negative, a serum
pregnancy test will be required.
Prior/Concomitant Therapy
4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or
with an agent directed to another stimulatory or co-inhibitory T-cell receptor
(e.g., CTLA-4, OX 40, CD137), and was discontinued from that treatment due to a
Grade 3 or higher irAE.
5. Has received prior systemic anti-cancer therapy including investigational agents or
has used an investigational device within 4 weeks prior to the first dose of study
treatment. Note: Participants who have entered the follow-up phase of an
investigational study may participate as long as it has been 4 weeks after the last
dose of the previous investigational agent.
6. Has received prior radiotherapy within 2 weeks of start of study treatment or have
had a history of radiation pneumonitis. Note: Participants must have recovered from
all radiation-related toxicities and not require corticosteroids. A 1-week washout
is permitted for palliative radiation (≤β weeks of radiotherapy) to non-CNS disease.
7. Has undergone prior allogeneic hematopoietic stem cell transplantation within the
last 5 years. (Participants who have had a transplant greater than 5 years ago are
eligible as long as there are no symptoms of GVHD).
8. Has had an allogeneic tissue/solid organ transplant.
9. Has received live live or live attenuated vaccines within 30 days prior to the first
dose of study treatment and while participating in the study. Note: Killed vaccines
are allowed. Note: Any licensed COVID-19 vaccine (including for Emergency use) in a
particular country is allowed in the study as long as they are mRNA vaccines,
adenoviral vaccines, or inactivated vaccines. These vaccines will be treated just as
any other concomitant therapy. Investigational vaccines (i.e., those not licensed or
approved for Emergency Use) are not allowed.
Diagnostic assessments
10. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior the first dose of study drug.
11. Has a known additional malignancy that is progressing or has required active
treatment within the past two (2) years. Note: Participants with basal cell
carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder
tumors (Ta, Tis & T1), second primary melanoma in situ, or carcinoma in situ, that
have undergone potentially curative therapy are not excluded.
12. Has known active CNS metastases and/or carcinomatous meningitis. Participants with
previously treated brain metastases may participate provided they are radiologically
stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging
(note that the repeat imaging should be performed during study screening),
clinically stable and without requirement of steroid treatment for at least 14 days
prior to first dose of study treatment.
13. Has severe hypersensitivity (≥Grade γ) to pembrolizumab and/or any of its
excipients, or to (immuno)cytokines IL2, TNF and/or any of its excipients
14. Has an active autoimmune disease that has required systemic treatment in past 2
years (i.e., with use of disease modifying agents, corticosteroids or
immunosuppressive drugs).
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency) is not considered a form
of systemic treatment and is allowed.
15. Has a history of (non-infectious) pneumonitis / interstitial lung disease that
required steroids or has current pneumonitis / interstitial lung disease.
16. Has an active infection requiring systemic therapy.
17. Has a history or current evidence of any condition, therapy, or laboratory
abnormality, or other circumstance that might confound the results of the study or
interfere with the participant's participation for the full duration of the study,
such that it is not in the best interest of the participant to participate, in the
opinion of the treating investigator.
18. Has a known psychiatric or substance abuse disorder that would interfere with the
participant's ability to cooperate with the requirements of the study.
19. Previous enrolment and randomization in this same study.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Memorial Sloan Kettering Cancer Center
Address:
City:
New York
Zip:
10065
Country:
United States
Status:
Recruiting
Contact:
Last name:
Danielle Marie Bello, MD
Email:
bellod@mskcc.org
Contact backup:
Last name:
Danielle Marie Bello, MD
Start date:
July 12, 2024
Completion date:
July 2028
Lead sponsor:
Agency:
Philogen S.p.A.
Agency class:
Industry
Collaborator:
Agency:
Merck Sharp & Dohme LLC
Agency class:
Industry
Source:
Philogen S.p.A.
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06284590
