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Malignant MelanomaEarly Phase 1NCT04223648

Programmed Cell Death 1 + Selected Cell Therapy With Durvalumab (MEDI4736) and Tremelimumab in Metastatic Melanoma

A Early Phase 1 study testing tremelimumab/durvalumab, ipilimumab/nivolumab and nivolumab monotherapy in people with Malignant Melanoma, run by Yale University.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial summary

The primary objective of this pilot study is to assess the feasibility of mobilizing PD-1+ T cells to the peripheral blood after a single treatment with tremelimumab/durvalumab in patients with treatment naïve metastatic melanoma. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Malignant Melanoma
What is being tested?
tremelimumab/durvalumab, ipilimumab/nivolumab and nivolumab monotherapy
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
No sites listed yet
Study dates
15 Aug 2020to Feb 2025
Phase
Early Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Untreated metastatic melanoma
  • A metastatic lesion at least 1.5 cm in diameter that can be removed surgically
  • Measurable or evaluable disease not including the resected lesion; at least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 target lesion (TL) at baseline. Tumor assessment by computed tomography (CT) scan or magnetic resonance imaging (MRI) must be performed within 28 days prior to enrollment
  • Capable of giving signed informed consent
  • Age >18 years at time of screening
  • Eastern Cooperative Oncology Group (ECOG) 0-1
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  • Body weight >30 kg
  • Hemoglobin ≥9.0 g/dL
  • Absolute neutrophil count (ANC ≥1.0 x 109/L (> 1000 per mm3)
  • Absolute lymphocyte count (ALC ≥0.5 x 109/L (> 500 per mm3) Platelet count ≥100 (or 75) x 109/L (>75,000 per mm3)
  • Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). (This will not apply to patients with confirmed Gilbert's syndrome)
  • Aspartate aminotransferase (AST) (SGOT)/Alanine aminotransferase (ALT) (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN
  • Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance
  • Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
  • Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
  • Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
  • Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
  • Must have a life expectancy of at least 12 weeks.

Who cannot join

  • Received prior treatment for metastatic melanoma
  • Received prior cell transfer therapy that included non-myeloablative or ablative chemotherapy
  • Received anti PD-1 immune therapy within prior 6 months
  • Any contraindication to neutropenia or thrombocytopenia for up to 2 weeks (no active major infection, no site of active, clinically significant bleeding)
  • Concurrent major medical illnesses
  • Any form of immunodeficiency
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  • Severe hypersensitivity to any of the agents used in this study
  • Contraindications for IL-2 administration
  • Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
  • Participation in another clinical study with an investigational product during the last 4 weeks
  • Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
  • Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
  • Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
  • Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab, tremelimumab, ipilimumab or nivolumab may be included only after consultation with the Study Physician.
  • Any concurrent chemotherapy, investigational product (IP), biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
  • Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable.
  • History of allogenic organ transplantation.
  • Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
  • Patients with vitiligo or alopecia
  • Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
  • Any chronic skin condition that does not require systemic therapy
  • Patients without active disease in the last 5 years may be included but only after consultation with the study physician
  • Patients with celiac disease controlled by diet alone
  • Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
  • History of another primary malignancy except for
  • Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence
  • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
  • Adequately treated carcinoma in situ without evidence of disease
  • History of leptomeningeal carcinomatosis
  • History of active primary immunodeficiency
  • Active infection including tuberculosis (TB) (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (HBV) (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
  • Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. The following are exceptions to this criterion:
  • Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
  • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
  • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
  • Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
  • Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or180 days after the last dose of durvalumab + tremelimumab combination therapy.
  • Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
  • Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment.
  • Judgment by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements.

About this study

Official title: A Pilot Study Using Programmed Cell Death 1 + Selected Cell Therapy With Durvalumab (MEDI4736) and Tremelimumab in Metastatic Melanoma

The primary objective of this pilot study is to assess the feasibility of mobilizing PD-1+ T cells to the peripheral blood after a single treatment with tremelimumab/durvalumab in patients with treatment naïve metastatic melanoma.

Read the detailed description

The primary objective of this pilot study is to assess the feasibility of mobilizing programmed cell death (PD-1)+ T cells to the peripheral blood after a single treatment with tremelimumab/durvalumab in patients with treatment naïve metastatic melanoma.

Secondary objectives are to evaluate the safety and clinical activity of administering a regimen of PD-1+ selected tumor infiltrating lymphocytes (TIL)/(Interleukin) IL-2, using a cell product manufactured in the Yale Advanced Cell Therapy Laboratories and assess for clinical activities in subjects with metastatic melanoma who are not responding or have progressed after receiving first-line therapy with 1 cycle of tremelimumab/durvalumab followed by 3 cycles of ipilimumab/nivolumab followed by nivolumab monotherapy as maintenance treatment.

Exploratory objective are to:

  1. assess the number of PD-1+ T cells in the tumor microenvironment before and after a single treatment with tremelimumab/durvalumab.
  2. conduct a preliminary assessment of the TCR clonotypes present in PD1+ cluster of differentiation 8 (CD8)+ cells (4-1BB, LAG-3, TIM-3, PD-1) versus PD1-CD8+ T-cells early in the expansion cultures and compare to clonotypes late in the final product and in peripheral blood lymphocytes (PBL) 1 and 2 months post infusion.
  3. assess neoantigens present in resected tumor and correlate T cell specificity for neoantigens from TIL and peripheral blood mononuclear cell (PBMC) populations stratified by PD-1 expression in these cell populations.
Being tested
tremelimumab/durvalumab, ipilimumab/nivolumab and nivolumab monotherapy
Medical subject headings
Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • tremelimumab/durvalumab, ipilimumab/nivolumab and nivolumab monotherapyDrug

    Subjects will receive 1 cycle of tremelimumab/durvalumab

    • Subjects will undergo resection to obtain tumor for generation of autologous tumor infiltrating lymphocytes (TIL) cultures and blood draw to obtain peripheral blood mononuclear cell (PBMC)s
    • TIL and PBMC will undergo immunoselection based on binding to an anti-programmed cell death 1 (PD-1) antibody and then will be expanded ex vivo.

    Subjects will receive 3 cycles of ipilimumab/nivolumab

    • Subjects will undergo staging with computer tomography (CT) chest/abdomen/pelvis and brain magnetic resonance imaging (MRI) or CT scan. subjects with stable disease will continue with nivolumab monotherapy; Subjects with progressive disease will proceed to cell therapy.
Study groups in NCT04223648
Study groupRoleWhat they receive
TreatmentExperimentalSubjects will receive 1 cycle of tremelimumab/durvalumab * Subjects will undergo resection to obtain tumor for generation of autologous tumor infiltrating lymphocytes (TIL) cultures and blood draw to obtain peripheral blood mononuclear cell (PBMC)s * TIL and PBMC will undergo immunoselection based on binding to an anti-programmed cell death 1 (PD-1) antibody and then will be expanded ex vivo. Subjects will receive 3 cycles of ipilimumab/nivolumab • Subjects will undergo staging with computer tomography (CT) chest/abdomen/pelvis and brain magnetic resonance imaging (MRI) or CT scan. subjects with stable disease will continue with nivolumab monotherapy; Subjects with progressive disease will proceed to cell therapy.
Receives: Drug: tremelimumab/durvalumab, ipilimumab/nivolumab and nivolumab monotherapy

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. PD1+ cell pharmacodynamic response in blood to tremelimumab/durvalumab treatment

    PD response is achieved if a patient achieves either 1) a 30% increase in PD-1+ T cells in the peripheral blood in subjects who have a minimum of 25 cells/microliter (uL) 9 at baseline, or 2) an absolute increase of at least 75 PD-1+ T cells/uL in subjects who do not have a minimum of 25 PD-1+ T cells/uL at baseline.

    Measured: up to 10 days post-enrollment.

Secondary outcomes (2)

  1. Safety including adverse events (AEs) and lab values

    Grading of AEs and lab values will be according to Common Terminology Criteria for Adverse Events 5.0.

    Measured: Up to 2 years post-enrollment.

  2. Overall response (OR)

    OR will be assessed per Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

    Measured: Up to 5 years post-enrollment.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted10 Jan 2020
  2. Study start15 Aug 2020 (estimated)
  3. Primary completionFeb 2022 (estimated)
  4. Study completionFeb 2025 (estimated)

Why it stopped: Funding

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Early Phase 1
Primary purpose
Basic science
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04223648
Sponsor's protocol ID
2000025925
Status last verified
Nov 2021
First submitted
19 Dec 2019
Last updated
22 Nov 2021
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Early Phase 1 study testing tremelimumab/durvalumab, ipilimumab/nivolumab and nivolumab monotherapy in people with Malignant Melanoma, run by Yale University.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 18 inclusion and 40 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 22 Nov 2021. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

PD1+ cell pharmacodynamic response in blood to tremelimumab/durvalumab treatment (time frame: up to 10 days post-enrollment.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04223648.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Nov 2021.

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