| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| ADVANCED OR RECURRENT SOLID TUMORS OR LYMPHOMAS |
|
| E.1.1.1 | Medical condition in easily understood language |
| ADVANCED OR RECURRENT SOLID TUMORS OR LYMPHOMAS |
|
| 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 | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| 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 | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10025310 |
| E.1.2 | Term | Lymphoma |
| 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 |
1. Evaluate the safety and tolerability of multiple doses of CX-072, administered as
monotherapy or in combination with ipilimumab or vemurafenib to subjects with
metastatic or locally advanced unresectable solid tumors or lymphomas.
2. Determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of:
• CX-072 as a monotherapy administered to PD-1/PD-L1 naïve subjects,
• CX-072 in combination with ipilimumab (concomitant schedule) administered
to PD-1/PD-L1 and CTLA-4 inhibitor naïve subjects,
• CX-072 in combination with ipilimumab (phased schedule) administered to
subjects that have had prior treatment with a PD-1/PD-L1 inhibitor, and
• CX-072 in combination with vemurafenib administered to PD-1/PD-L1 naïve
subjects. |
|
| E.2.2 | Secondary objectives of the trial |
1. Obtain preliminary evidence of anti-cancer activity on the basis of objective responses in
subjects treated with CX-072 as monotherapy or when administered in combination with
ipilimumab or vemurafenib:
• Objective response rate by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1 and irRECIST),
• Objective response rate by modified immune-related response criteria as defined in the Common Core Document or Modified Cheson/Lugano Classification for Lymphomas,
• Time to response (TTR)
• Duration of response (DOR)
• Progression-free survival (PFS)
Similarly, obtain preliminary evidence of anti-cancer activity on the basis of objective
responses in subjects treated with CX-072 as monotherapy in advanced or metastatic
gastric and gastroesophageal junction (GEJ) tumors
2. Characterize the immunogenicity of CX-072
3. Characterize the preliminary single and multi-dose pharmacokinetic profile of CX-072
4. Assess overall survival (OS) in subjects receiving CX-072 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically confirmed diagnosis of the following metastatic or advanced unresectable
tumors that progressed on standard therapy:
• Part A: any metastatic or advanced unresectable solid tumor or lymphoma, measurable or non-measurable disease allowed, no further standard of care therapy available
o Naïve to treatment with a PD-1/PD-L1 inhibitor
o No PD-1/PD-L1 inhibitor therapy available for their specific disease in the country where they are being treated
• Part B1: any metastatic or advanced unresectable solid tumor or lymphoma, measurable or non-measurable disease allowed, no further standard of care therapy available
o Naïve to treatment with a PD-1/PD-L1 inhibitor
o No PD-1/PD-L1 inhibitor therapy available for their specific disease in the country where they are being treated
o Naïve to treatment with a CTLA-4 inhibitor
• Part B2: any metastatic or advanced unresectable solid tumor or lymphoma with measurable disease allowed, no further standard of care therapy available
o Previous treatment with a PD-1/PD-L1 inhibitor
o Discontinued treatment with PD-1/PD-L1 inhibitor for reasons other than toxicity
o Naïve to treatment with a CTLA-4 inhibitor
o Agreement to participate in biomarker analysis and have tumor suitable for biopsy (only in cohorts receiving CX-072 + 3 mg ipilimumab [but not 10 mg ipilimumab])
• Part C: metastatic or advanced unresectable melanoma with BRAF V600E mutation-positive as detected by a diagnostic approved test (in the region where the subject is treated), measurable or non-measurable disease allowed
o Naïve to treatment with BRAF-inhibitor
o Naïve to treatment with a PD-1/PD-L1 inhibitor
• Part D: metastatic or advanced unresectable gastric and GEJ cancers, measurable disease required
o Naïve to treatment with a PD-1/PD-L1 inhibitor
o Subjects that have had their tumor tissue analyzed for PD-L1 may not enroll if they are known to be PD-L1 negative. (Subjects known to be PD-L1 positive or that have never undergone PD-L1 tumor assessment are eligible.)
o HER2 negative (FISH or IHC testing acceptable)
o For GEJ tumors with significant esophageal component, esophageal cancer Siewert II/III
o Subjects must be ineligible for platinum based or fluorpyrimidine based chemotherapy or approved ramucirumab based regimen or have already received these therapies. Subjects must have had standard of care surgery for their cancer, if applicable.
2. Agreement to provide mandatory archival tissue or fresh biopsy. A tumor biopsy is required at baseline if there is no other record of histological diagnosis of tumor.
3. For subjects in Part B2 receiving 3 mg/kg of ipilimumab and those who agree to participate in the biomarker analysis and who have a tumor site that is safe to biopsy, subjects must have a biopsy within 90 days of study entry and be willing to undergo at least one on-treatment tumor biopsy.
4. Subjects with treated brain metastases are eligible if the brain metastases are stable and the subject does not require radiation therapy, or steroids. Active screening for brain metastases (eg, brain computed tomography [CT] or magnetic resonance imaging [MRI]) is not required.
5. At least 18 years of age.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
7. Anticipated life expectancy of at least 3 months.
8. Screening laboratory values must meet the following criteria:
• White blood cells (WBCs) > 2000/µL or 2.0 × 10(-9)/L;
• Neutrophils ≥ 1500/µL or 1.5 × 10(-9)/L;
• Platelets ≥ 100 × 10(-3)/µL or 100 × 10(-9)/L;
• Hemoglobin ≥ 9.0 g/dL (may have been transfused) or 90.0 g/L;
• Creatinine ≤ 2 mg/dL or 176.8 μmol/L;
• Aspartate aminotransferase (AST) ≤ 2.5 × upper limit of normal (ULN); ≤ 5 × ULN for subjects with liver metastasis; < 3 × ULN for subjects in Part C (vemurafenib + CX-072). No upper limit for subjects with HCC or pancreatic cancer;
• Alanine aminotransferase (ALT) ≤ 2.5 × ULN; ≤ 5 × ULN for subjects with liver metastasis; < 3 × ULN for subjects in Part C (vemurafenib + CX-072). No ULN for subjects with HCC or pancreatic cancer;
• Total bilirubin within upper limit of normal (unless diagnosed with Gilbert’s syndrome, those subjects must have a total bilirubin < 3.0 mg/dL or 51.3 μmol/L). No upper limit for subjects with HCC;
• Amylase and Lipase 1.5 × ULN. No upper limit for subjects with pancreatic cancer.
9. Women of childbearing potential and males must agree to use a highly effective method of contraception (hormonal or vasectomy or abstinence) prior to study entry, while on study drug, and for a period of 90 days following the last treatment.
10. The ability to understand and the willingness to sign a written informed consent document and adhere to study schedule and prohibitions. |
|
| E.4 | Principal exclusion criteria |
1. Prior therapy with a chimeric antigen receptor (CAR) T-cell containing regimen.
2. Baseline QTc is > 470 ms in the vemurafenib treatment arm, or taking any medication known to prolong the QT interval.
3. Prior history of myocarditis irrespective of the cause.
4. Treatment with strong CYP3A4 inhibitors or inducers, as well as use of CYP1A2 substrates with a narrow therapeutic window assigned to the vemurafenib treatment arm.
http://medicine.iupui.edu/clinpharm/ddis/main-table/
5. History of severe allergic or anaphylactic reactions to human monoclonal antibody therapy or known hypersensitivity to any Probody Tx.
6. Active or history of uveal, mucosal, or ocular melanoma is excluded in Parts B2 and C.
7. Subjects with gastrostoma are excluded in Part D.
8. Human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS)-related illness, chronic hepatitis B or C.
9. History of or current active autoimmune diseases, including but not limited to inflammatory bowel diseases, rheumatoid arthritis, autoimmune thyroiditis, autoimmune hepatitis, systemic sclerosis, systemic lupus erythematosus, autoimmune vasculitis, autoimmune neuropathies, or type 1 insulin dependent diabetes mellitus.
10. History of syndrome or medical condition(s) that requires systemic steroids (> 10 mg daily prednisone equivalents) or immunosuppressive medications.
11. History of allogeneic tissue/solid organ transplant, prior stem cell or bone marrow transplant.
12. Chemotherapy, biochemotherapy, radiation or immunotherapy or any investigational treatment within 30 days prior to receiving any study drug.
13. Major surgery (requiring general anesthesia) within 3 months or minor surgery (excluding biopsies conducted with local/topical anesthesia) or gamma knife treatment within 14 days (with adequate healing) of administration of any study drug.
14. Unresolved acute toxicity of the NCI CTCAE v4.03 Grade > 1 (or baseline, whichever is greater) from prior anti-cancer therapy. Alopecia and other non-acute toxicities are acceptable.
15. History of malignancy that is active within the previous 2 years except for localized cancers that are not related to the current cancer being treated and considered to have been cured and in the opinion of the Investigator, present a low risk for recurrence. These exceptions include, but are not limited to, basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix or breast.
16. Received a live vaccine within 30 days prior to first dose of study drug.
17. Known pre-existing condition of age-related macular degeneration (AMD).
18. Uncontrolled intercurrent illness, including, but not limited to, ongoing or active infection (including fever within 48 hours of screening), symptomatic congestive heart failure (ie, New York Heart Association Class III or IV), unstable angina pectoris, clinically significant and uncontrolled cardiac arrhythmia, non-healing wound or ulcer, or psychiatric illness/social situations that would limit compliance with study requirements.
19. Participating in an ongoing clinical study involving treatment with medications, radiation or surgery.
20. Women who are pregnant or breastfeeding. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Assessment of dose limiting toxicity (DLT)
2. Establishment of the maximum tolerated dose (MTD). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Objective response rate by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1 and irRECIST)
2. Objective response rate by modified immune-related response criteria as defined in the Common Core Document or Modified Cheson/Lugano Classification for Lymphomas
3. Time to response (TTR),
4. Duration of response (DOR)
5. Progression-free survival (PFS) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | 5 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
| France |
| Germany |
| Hungary |
| Netherlands |
| Poland |
| Spain |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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