| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HLA-A*02:01-Positive Participants with Advanced PRAME-Positive Cancers. Study IMC-F106C-101 will enroll participants with advanced cancers, including unresectable or metastatic melanoma, ovarian carcinoma, uterine carcinoma, non-small cell lung cancer (NSCLC), small-cell lung cancer (SCLC), triple negative breast cancer (TNBC), and urothelial carcinoma, that are relapsed from, refractory to, or intolerant of standard treatment regimens |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with advanced cancer, unresectable or metastatic melanoma, ovarian & uterine carcinoma, non-small cell lung and small-cell lung cancer, triple negative breast cancer & urothelial carcinoma |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025665 |
| E.1.2 | Term | Malignant melanoma of skin stage unspecified |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10042863 |
| E.1.2 | Term | Synovial sarcoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064467 |
| E.1.2 | Term | Urothelial carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10075566 |
| E.1.2 | Term | Triple negative breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10046769 |
| E.1.2 | Term | Uterine carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033131 |
| E.1.2 | Term | Ovarian carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary (Phase 1): To assess the safety and tolerability of IMC-F106C and identify the MTD and/or RP2D for the D1D, D8D, and CDD of IMC-F106C as:
o A monotherapy in advanced solid tumors
o In combination with a checkpoint inhibitor in advanced solid tumors
Primary (Phase 2): To characterize the initial efficacy of IMC-F106C as a monotherapy in selected advanced solid tumors |
|
| E.2.2 | Secondary objectives of the trial |
To assess the antitumor efficacy of IMC-F106C as a monotherapy and in combination with a checkpoint inhibitor
To characterize the PK profile of IMC-F106C as a monotherapy and in combination with a checkpoint inhibitor
To evaluate the frequency of antibody formation against IMC-F106C following treatment with IMC-F106C as a monotherapy and in combination with a checkpoint inhibitor
To determine pharmacodynamic changes in peripheral cytokines and lymphocyte counts following treatment with IMC-F106C |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants are eligible to be included in the study only if all the following criteria apply:
1. Participant must be ≥ 18 years of age, inclusive, at the time of signing the ICF
2. Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 at start of treatment
3. HLA-A*02:01-positive (testing by central laboratory)
4. PRAME-positive tumor, defined as one of the following:
a.Documentation of histologically confirmed diagnosis of a tumor type in which PRAME is expressed in >70% of tumors (eg, cutaneous melanoma, serous ovarian carcinoma, or endometrial carcinoma). Note: availability of an adequate tumor biopsy (as defined in the study Laboratory Manual) for retrospective PRAME testing must be confirmed during Screening
b.For tumor types where the frequency of PRAME expression is ≤70% (eg, NSCLC, SCLC, urothelial carcinoma, TNBC), and tumor types where the frequency of PRAME expression is unknown, tumor PRAME expression must be documented based on testing by the study central laboratory
5. Participants who are enrolling in biomarker cohorts must have disease that is amenable to biopsy and consent to undergo tumor biopsies during Screening and treatment
6. Participants who are enrolling in Phase 1 must have evaluable disease, and participants who are enrolling in Phase 2 must have measurable disease according to RECIST v1.1
7. Participants with metastatic or unresectable solid tumors are eligible for Arm A and Arm B. Participants must meet the indication-specific histology/tumor site requirements specified below:
- R/M melanoma: All primary sites allowed, including cutaneous, mucosal, and uveal
- R/M ovarian carcinoma: All histologies allowed; Includes fallopian tube and primary peritoneal cancers
- R/M uterine carcinoma: All histologies allowed
- R/M NSCLC: All histologies allowed
- R/M SCLC: All histologies allowed, including high-grade neuroendocrine large cell lung cancer
- R/M breast cancer: Triple-negative breast cancer
- R/M urothelial carcinoma: Tumors are allowed from renal pelvis, ureters, urinary bladder, and urethra
- Other R/M solid tumors: All histologies allowed (pending availability of a validated assay to assess tumor PRAME expression)
8. Participants must have relapsed from, are refractory to, or intolerant of all therapies listed in the protocol for their indication and study phase. These therapies must have been given for unresectable/metastatic disease or given in the adjuvant setting if disease progression occurred during or within 6 months of completing adjuvant therapy. There is no maximum limit on the number of prior therapies received. Biomarker testing requirements are shown in Table 13 in the protocol; additional biomarker test results may be requested if available but are not required for eligibility
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|
| E.4 | Principal exclusion criteria |
- 1. Presence of untreated or symptomatic CNS metastases, leptomeningeal disease, or cord compression: a. Treated CNS lesions must be radiographically stable for ≥ 2 weeks after intervention (surgery and/or radiation); b. Participants must be neurologically stable off systemic corticosteroids for at least 2 weeks prior to enrollment.
- 2. Bowel obstruction within 3 months prior to the planned first dose of study treatment.
- 3. Ongoing ascites requiring recurrent paracentesis (ie, at least twice within 28 days prior to the planned first dose of study treatment).
- 4. Presence of NCI CTCAE ≥ Grade 2 toxicity due to prior cancer therapy.
- 5.Participants enrolling in Arm B with prior immunotherapy exposure must not have experienced immune-mediated AE (imAE) meeting any of the following criteria: a. Grade 4 imAE; b. imAE resulting in the discontinuation of any prior immunotherapy; c. imAE that failed initial immunosuppressive intervention; d. imAE that recurred upon rechallenge; e. Pneumonitis that required oral or IV steroids; f. Any neurological, ocular, or renal imAE.
- 6. Receipt of anticancer therapy for the disease under study within the following times prior to the first planned dose of study intervention: a. Cellular therapies (eg, T-cell therapies): 90 days; b.Cytotoxic T-lymphocyte associated protein-4 (CTLA-4)-targeted immunotherapies (eg, ipilimumab): 28 days; c. All other immunotherapies, including PD-(L)1targeted immunotherapies (eg,atezolizumab, pembrolizumab): 21 days; d. All other systemic therapies: 14 days; e. Radiotherapy: 14 days(excepting palliative radiotherapy to a limited field, which may be administered within 14 days, eg, for a focally painful tumor mass).
- 7. Participant with an out-of-range Screening laboratory values defined as shown below. NOTE: Hematology evaluations must be performed ≥ 7 days from any blood or blood product transfusion and ≥ 14 days from any dose of hematologic growth factor: a. Glomerular filtration rate (calculated using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula, see Section 10.3) < 50 mL/min; b. Urine protein ≥2+, unless reflex testing confirms urine protein < 1 g/24h; c. Total bilirubin > 1.5 ×ULN, participants with Gilbert's syndrome are excluded if total bilirubin > 3.0 × ULN or direct bilirubin > 1.5 × ULN); d. Alanine aminotransferase > 3 × ULN; e. Aspartate aminotransferase > 3 × ULN; f. Albumin < 3.0 g/dL; g. Absolute neutrophil count < 1.0 × 109/L; h. Absolute lymphocyte count < 0.5 × 109/L; i. Platelet count < 75 × 109/L; j. Hemoglobin < 9 g/dL; k. Morning cortisol < lower limit of normal (unless the participant has asymptomatic adrenal insufficiency and is receiving stable replacement doses).
- 8. High risk of venous thromboembolism, defined as a score of ≥ 3 points based on the criteria below (Khorana, 2008): a. Site of cancer is lung, gynecologic, or genitourinary (1 point); b. Platelet count > 350 × 109/L (1 point); c. Hemoglobin < 10 g/dL or use of erythropoiesis-stimulating agents (1 point); d. Leukocyte count > 11 × 109/L (1 point); e. Body mass index ≥35 kg/m2 (1 point).
- 9. Clinically significant pulmonary disease or impaired lung function, including any of the following: a. Pneumonitis (Grade 2 or higher) within 12 months of the first dose of study treatment; b. Ongoing requirement for intermittent or continuous supplemental oxygen; c. Resting oxygen saturation at Screening <94% on room air; d. Thromboembolic event (eg, deep vein thrombosis or pulmonary embolism) within 12 months of the first dose of study treatment
- 10. Clinically significant cardiac disease or impaired cardiac function, including any of the following: a. Congestive heart failure (New York Heart Association Class ≥ 3); b. Uncontrolled hypertension (consistent findings [as defined in Section 8.2.3] of systolic blood pressure [BP] > 160 mmHg or diastolic BP > 110 mmHg); c. History of ventricular arrhythmia currently requiring medical treatment; d. Uncontrolled atrial fibrillation; e. Electrocardiogram QT interval corrected for heart rate by Fridericia's method (QTcF) > 470 msec during Screening obtained on triplicate ECGs or known history of congenital prolonged QT syndrome; f. Acute myocardial infarction or unstable angina pectoris ≤ 6 months prior to Screening; g. Left ventricular ejection fraction (LVEF) < 50% on Screening echocardiogram; h. Cardiac troponin (I or T based on institutional standard) > ULN at Screening.
-11. Current or known history of any clinically significant coagulopathy such as Factor V Leiden mutation or prothrombin G20210A mutation, anti-phospholipid syndrome, or recurrent thrombotic /thromboembolic event despite therapeutic anti-coagulation. PLEASE SEE THE PROTOCOL FOR REMAINDER OF EXCLUSION CRITERIA
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary (Phase 1):
• Incidence of DLTs
• Incidence and severity of AEs and SAEs
• Changes in safety laboratory parameters, vital signs, and electrocardiogram (QTcF)
• Incidence of dose interruptions, reductions, and discontinuations
Primary (Phase 2):
• BOR as determined by RECIST v1.1
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Within Each Treatment Cycle Defined As Every 21 Days and In Accordance With Section 1.3.2 and Table 2 (Schedule of Assessments, Treatment Stage) of The Study Protocol |
|
| E.5.2 | Secondary end point(s) |
Secondary
• BOR by RECIST v1.1 (Phase 1 only)
• PFS and DOR by RECIST v1.1
• OS
• IMC-F106C serum PK parameters (eg, AUC, Cmax, Tmax, t1/2) after single and multiple doses
• Incidence of anti-IMC-F106C antibody formation
• Change in peripheral blood lymphocyte counts and serum cytokine concentrations over time |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Within Each Treatment Cycle Defined As Every 21 Days and In Accordance With Section 1.3.2 and Table 2 (Schedule of Assessments, Treatment Stage) of The Study Protocol |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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