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IMP-MEL: IMM60 & pembrolizumab in Melanoma and NSCLC

IMP-MEL Trial Logo.jpg

FULL TITLE

A phase 1 first-in-human dose finding/randomised phase 2 study of IMM60 and pembrolizumab in advanced melanoma and NSCLC

Chief Investigator: Professor Mark Middleton

Sponsor: University of Oxford

STUDY DESIGN

This will be a randomised phase 1/2 trial. Initial safety will be assessed in a multiple ascending dose cohort for IMM60, then for IMM60 + pembrolizumab. The Trial Management Group (TMG) will review the Phase 1 data, the current standard of care and feasibility to make a recommendation on Phase 2 cohorts. Potential arms in the Phase 2 component include: pembrolizumab alone & IMM60+pembrolizumab for NSLC patients; and pembrolizumab alone, IMM60+pembrolizumab, and additional IMM60 alone cohort for melanoma patients.

STUDY POPULATION

This clinical trial aims to determine the synergistic effect of IMM60 and pembrolizumab, compared to pembrolizumab alone in patients with melanoma and non-small cell lung cancer, for which pembrolizumab is already licensed as a standard of care. The trial will also evaluate if IMM60 can restore sensitivity to patients with melanoma resistant to pembrolizumab as well as ascertain if IMM60 can promote PDL1 expression in PDL1 non expressing small cell lung cancer.

STUDY SCHEMA:                            

Phase 1 Schema:

IMP-MEL_Phase1Schema.jpg

 

Phase 2 Schema:

IMP-MEL_Phase2Schema.jpg

STUDY STATUS

STUDY STATUS

Recruiting

TARGET RECRUITMENT

Total 100 patients (Phase 1: 18, Phase 2: 82)

PARTICIPATING SITE

Churchill Hospital – Oxford University Hospital NHS Trust

INCLUSION CRITERIA

1.  Aged ≥18 years
2.  Melanoma arms:

    •  Unresectable stage 3 or 4, histologically proven cutaneous or unknown primary melanoma
    •  Result of BRAF mutation status is available

Phase 1:

 IMM60 dose escalation arm:

    • Patients progressing through at least one line of immunotherapy. For those patients with BRAF mutant tumours, progression through BRAF/MEK inhibitor treatment and at least one line of immunotherapy

 IMM60 + pembrolizumab dose safety arm:

    • Patients not previously exposed to a PD-1 inhibitor who fulfill NHS criteria for the funding of Pembrolizumab as determined by the Cancer Drugs Fund (CDF) (see appendix 3) with the exception that pembrolizumab will not be administered as monotherapy.

Phase 2:

    • Melanoma Cohort 1: Patients with metastatic disease not previously exposed a PD-1 inhibitor
    • Melanoma Cohort 2: Patients with metastatic disease previously exposed to a PD-1 inhibitor

Patients in Melanoma Cohort 1 must meet CDF criteria for funding for pembrolizumab, Melanoma Cohort 2 patients do not need to meet these criteria (IMM60 administration as monotherapy)

 3. NSCLC arms

    • Histologically confirmed stage 4 non-small cell lung cancer
    • Patients with adenocarcinoma histology must not have sensitizing EGFR or ROS1    mutations or ALK translocations
    • No prior systemic therapy for advanced disease. Previous chemotherapy in the context of adjuvant treatment is permissible as long as the treatments were completed at least 6 months prior to consent.
    • Patient in non-small cell lung cancer arms must have a PDL1 assessment prior to randomization. PDL1 assessment must be performed in an approved laboratory.

Phase 1: IMM60 dose escalation arm:

    • Progression through systemic therapy consisting of at least platinum based chemotherapy and immunotherapy (either sequentially or in combination)

IMM60 + pembrolizumab dose safety arm:

    • First line treatment for patients who fulfil NHS criteria for the funding of Pembrolizumab as determined by the Cancer Drugs Fund (CDF) (see appendix 3) with the exception that pembrolizumab will not be administered as monotherapy.

Phase 2:

    • NSCLC Cohort 1: Metastatic NSLC, PDL1 +ve (PDL1 <50%) not previously exposed to a PD-1 inhibitor
    • NSCLC Cohort 2: Metastatic NSLC, PDL1 –ve (PDL1 <50%) not previously exposed to a PD-1 inhibitor but pre-treated with at least one line of systemic treatment

Patients in NSCLC Cohorts 1 must meet CDF criteria for funding for pembrolizumab, with the exception of pembrolizumab administration as monotherapy

4.   At least 1 lesion, not previously irradiated, that can be accurately measured on CT or MRI as defined by RECIST 1.1 criteria. Cutaneous lesions and other superficial lesions detectable only by physical examination are not measurable lesions however may be considered non-target lesions.

5.  ECOG performance score of 0 or 1.

6.  Life expectancy of at least 12 weeks.

7.  The patient is willing to give consent to the study and able to comply with the protocol for the duration of the study, including scheduled follow-up visits and examinations.

 8.  Prior systemic treatments must have been completed at least 4 weeks prior to enrolment and all toxicities have either returned to baseline or resolved to < grade 1 with the exception of alopecia. For patients with melanoma previously treated with a target tyrosine kinase inhibitor, prior treatment within 2 weeks is acceptable

9.  Haematological and biochemical indices within the ranges shown below:

Lab Test

Value required

Haemoglobin (Hb)

>10g/dL

White Blood Count (WBC)

 >3x109/L

Platelet count

>100x109/L

Absolute Neutrophil count

>1.5x109/L

Serum bilirubin

≤ 1.5 x ULN

Or direct bilirubin ≤ ULN for patients with total bilirubin concentration > 1.5 x ULN

AST (SGOT) or ALT

≤ 2.5 x ULN

≤5 x ULN for patients with liver metastases

Creatinine clearance (Cockcroft-Gault)

>50 ml/min

International Normalized Ratio (INR) or Prothrombin Time (PT)

 

Activated Partial Thromboplastin Time (aPTT)

≤1.5 X ULN unless patient is receiving anticoagulant therapy
as long as PT or PTT is within therapeutic range of intended use of anticoagulants

≤1.5 X ULN unless patient is receiving anticoagulant therapy
as long as PT or PTT is within therapeutic range of intended use of anticoagulants

 

EXCLUSION CRITERIA

EXCLUSION CRITERIA

  1. Any anti-cancer therapy (including radiotherapy and participation in other clinical trials) within 28 days except tyrosine kinase inhibitors in which case 2 weeks prior to Day 1.
  2. Any unresolved toxicity from prior anti-cancer therapy that is greater than CTCAE grade 2.
  3. Pregnant or breastfeeding women. Female patients must have a negative urinary or serum pregnancy test or have evidence of post-menopausal status (defined as absence of menstruation for > 12 months, bilateral oophrectomy or hysterectomy).
  4. Patients with non-small cell lung cancer with large volume tumour burden, who, at the  investigator’s discretion are considered more appropriate for systemic chemotherapy.
  5. Patients of reproductive potential who are not willing to use adequate contraceptive measures for the duration of the study and for 120 days after last dose of trial drug (both male and female patients.)
  6. Known severe hypersensitivity reactions to anti-PD1 agents or has received prior therapy with an agent directed towards PD1/PDL1 or 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 (except IMM60 monotherapy cohort who can have received prior PD1).
  7. Ocular or mucosal malignant melanoma.
  8. Another active malignancy within the past two years (Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded. Also, prostate, breast and neuroendocrine tumours that are stable on hormonal treatment for a period of 1 year or more without the need to adjust dose are not excluded.)
  9. Evidence of brain metastases, unless surgically resected/stereotactic radiosurgery treated brain metastasis and stable off treatment, including steroids, for 8 weeks.
  10. Clinically significant and uncontrolled major medical condition(s): such as active infection, bleeding diathesis.
  11. Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV. Testing is not required unless clinically indicated.
  12. Cardiac conditions, defined by uncontrolled hypertension (BP>160/100 despite treatment), heart failure NYHA class 2 or above, myocardial infarction within 6 months or angina requiring nitrate therapy more than once a week.
  13. Previous treatment with anti -PD1 antibodies for experimental arms: (Melanoma Cohort 2 for melanoma in the phase 2 trial) or all cohorts in NSCLC.
  14. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
  15. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
  16. Has an active infection requiring systemic therapy.
  17. Prior treatment with IMM60.
  18. Patients with an active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids (in dosing exceeding 10 mg daily of prednisone equivalent) or immunosuppressive agents. Patients with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Patients that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Patients with hypothyroidism stable on hormone replacement will not be excluded from the study.
  19. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. 

PRIMARY OBJECTIVE

Phase 1: To characterize the safety and confirm the MTD of IMM60 alone and in combination with pembrolizumab, in patients with advanced malignant melanoma or PDL1 +ve (PDL1 ³ 50%) NSCLC

Phase 2: To report the progression free survival rate at 12 months for pembrolizumab alone versus IMM60 + pembrolizumab in patients with advanced PDL1 +ve (PDL1 ³ 50%) NSCLC or Melanoma

Key dates

  • Opened to recruitment  1st June 2021 
  • Expected study end dates:  
      • Phase I - 31st  December 2021
      • Phase II –31st December 2023