Study of the Efficacy of Intratumoral L19IL2 or L19TNF or L19IL2/L19TNF, in Combination with Pembrolizumab, in Unresectable Melanoma Patients

NCT06284590 | Recruiting Phase 2 DMC FDA Drug

• 3 other identifiers: PH-ICKPD1-02/21MK-3475-F20KEYNOTE-F20
• Study Type: interventional
• Target: 162
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Melanoma Stage III; Melanoma Stage IV

Outcome Measures

Primary Outcomes (1)

• Confirmed Objective Response Rate (ORR)

  Objective Response Rate (ORR = CR + PR) in all three arms to demonstrate the efficacy of intralesional treatment with immunocytokines (L19IL2, or L19TNF, or L19IL2/L19TNF), in combination with the systemic anti-PD1 pembrolizumab, to induce objective responses in advanced melanoma patients with resistance to or progressing upon anti-PD1 checkpoint inhibitors. The primary analysis will be performed in the Intention-to-Treat population (ITT). Assessed during Tumor Assessment (TA) visits.

  Evaluated over a period of up to 2 years after first intralesional treatment. TA visits will be performed at week 12, 18, 24, 36, 48, 64, 80 and 96 after first intralesional treatment or until confirmed progression or death, whichever occurs first

Secondary Outcomes (27)

• Best overall response (BOR)

  From the date of first treatment until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 96 Weeks

• Duration of Response (DoR)

  From the date of first treatment until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 36 Months

• Pathological response

  At 18 weeks after first treatment

• Confirmed ORR

  From date of first administration, after a period of up to 2 years

• Progression-free survival (PFS)

  From the date of randomization until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 96 Weeks

Study Arms (3)

Systemic pembrolizumab in combination with intralesional L19IL2 (Arm 1)

EXPERIMENTAL

Two-weeks screening period and a 4-weeks open-label intralesional treatment period with L19IL2. Pembrolizumab will be administered by i.v. infusion on the first day of intralesional treatment with L19IL2, 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.

Drug: L19IL2; Drug: KEYTRUDA®

Systemic pembrolizumab in combination with intralesional L19TNF (Arm 2)

EXPERIMENTAL

Two-weeks screening period and a 4-weeks open-label intralesional treatment period with L19TNF. Pembrolizumab will be administered by i.v. infusion on the first day of intralesional treatment with L19TNF, 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.

Drug: L19TNF; Drug: KEYTRUDA®

Systemic pembrolizumab in combination with intralesional L19IL2/L19TNF (Arm 3)

EXPERIMENTAL

Two-weeks screening period and a 4-weeks open-label intralesional treatment period with L19IL2/L19TNF. Pembrolizumab will be administered by i.v. infusion on the first day of intralesional treatment with L19IL2/L19TNF, 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.

Drug: L19IL2/L19TNF; Drug: KEYTRUDA®

Interventions

L19IL2 DRUG

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.

Also known as: bifikafusp alfa

Systemic pembrolizumab in combination with intralesional L19IL2 (Arm 1)

L19TNF DRUG

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.

Also known as: onfekafusp alfa

Systemic pembrolizumab in combination with intralesional L19TNF (Arm 2)

L19IL2/L19TNF DRUG

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.

Also known as: Daromun

Systemic pembrolizumab in combination with intralesional L19IL2/L19TNF (Arm 3)

KEYTRUDA® DRUG

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®.

Also known as: pembrolizumab

Systemic pembrolizumab in combination with intralesional L19IL2 (Arm 1); Systemic pembrolizumab in combination with intralesional L19IL2/L19TNF (Arm 3); Systemic pembrolizumab in combination with intralesional L19TNF (Arm 2)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
• Be \> or equal to 18 years of age on day of signing informed consent.
• 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.
• 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.
• 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.
• 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.
• 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).
• 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).
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Have adequate organ function as defined in the following table. Specimens must be collected within 14 days prior to the start of study treatment.
• 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
• 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.

You may not qualify if:

• Participants are excluded from the study if any of the following criteria apply:
• Medical Conditions
• 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.
• Uveal melanoma or mucosal melanoma or melanoma with unknown primary.
• 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
• 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.
• 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.
• 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.
• 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).
• Has had an allogeneic tissue/solid organ transplant.
• 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
• 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.
• 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.

Sponsors & Collaborators

• Philogen S.p.A.: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

RECRUITING

MeSH Terms

Conditions

Melanoma

Interventions

daromun; pembrolizumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Danielle Bello

  Memorial Sloan Kettering Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Giuliano Elia, PhD

CONTACT

+39 057717816; regulatory@philogen.com

Marco Taras

CONTACT

+39 057717816; regulatory@philogen.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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

Study Record Dates

• First Submitted: January 26, 2024
• First Posted: February 29, 2024
• Study Start: July 12, 2024
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): July 1, 2028
• Last Updated: October 26, 2024

Record last verified: 2024-10

Locations

US (1)