| 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 | 21.1 |
| 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 | 20.0 |
| 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 |
For Parts A through C:
1.Evaluate safety & tolerability of multiple doses of CX-072, administered as monotherapy or in combination with ipilimumab (IPI) or vemurafenib (VEM) to patients with metastatic or locally advanced
unresectable solid tumors or lymphomas 2.Determine MTD and DLTs of:
•CX-072 as a monotherapy administered to PD-1/PD-L1 naive patients
•CX-072 in combination with IPI administered to PD-1/PD-L1 & CTLA-4 inhibitor naive patients
•CX-072 in combination with IPI administered to patients that have had prior treatment with PD-1/PD-L1 inhibitor
•CX-072 in combination with VEM administered to PD-1/PD-L1 naive patients
For Parts D & E: to obtain evidence of efficacy of CX-072 monotherapy,respectively, via the ORR according to RECIST v 1.1, as assessed by Investigator(Part D) or by independent review facility(Part E)
For Long-term extension: maintain CX-072 treatment for patients experiencing ongoing clinical benefit & to assess long-term safety of CX072
monotherapy |
|
| E.2.2 | Secondary objectives of the trial |
Part:A-C:
1.Obtain preliminary evidence of anti-cancer activity on the basis of objective responses (OR)in pts treated with CX-072 as monotherapy or in combination with ipilimumab/vemurafenib:•ORR by RECIST v 1.1•OR rate by modified immune-related response criteria defined in the CommonCore or Modified Cheson/Lugano Classification for Lymphomas•TTR and DOR• PFS
2.Characterize incidences of ADA against CX-072 and ipilimumab
3.Characterize the single/multidose PK profile of CX-072 administered alone and in combination:CX-72,ipilimumab,vemurafenib
4.OS in pts receiving CX-072
Part:D-E:
1.Characterize the efficacy of CX-072 monotherapy by:•DOR as assessed by Investigator (PartD) or by IRF(PartE)•ORR by RECIST v1.1 by PD-L1 expression (PartE)•ORR by modified irRECIST defined in the CommonCore•PFS
2.Evaluate safety, tolerability of CX-072 administered as monotherapy
3.Characterize incidences of ADAs against CX-072
4.Characterize the PK profile of CX-072 5.OS in pts receiving CX-072 |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
CTMX-M-072-001 Protocol Modul Substudy titled: "89ZR-CX-072-PET IMAGING IN SUBJECTS WITH LOCALLY ADVANCED OR METASTATIC SOLID TUMORS OR MALIGNANT LYMPHOMA" dated on 23 October 2017 and applicable in the Netherlands only.
Primary Objective:
1. The primary objective of this substudy is to evaluate the whole body distribution of 89Zr-CX-072 in subjects with locally advanced or metastatic solid tumors or malignant lymphoma.
Secondary Objectives:
1. To evaluate the correlation of 89Zr-CX-072 tumor uptake with PD-L1 expression as assessed in archival or fresh tumor tissue;
2. To assess the heterogeneity of 89Zr-CX-072 tumor uptake within and between patients;
3. To describe the safety of 89Zr-CX-072 alone or in combination with CX-072;
4. To evaluate the relationship between tumor uptake of 89Zr-CX-072 and subject response as measured by overall response rate (ORR) in the main study (CTMX-M-072-001);
5. To characterize the incidence of anti-drug antibodies (ADA) against CX-072; and
6. To characterize the PK profile of 89Zr-CX-072 and CX-072.
Exploratory Objectives:
1. To evaluate the relationship between 89Zr-CX-072 normal and tumor tissue levels with circulating 89Zr-CX-072 and CX-072 levels;
2. To evaluate Probody molecule activation status and protease activity within the tumor microenvironment; and
3. To evaluate the presence of PD-L1, the target of CX-072, in patient tumors to assess utility as a predictive marker of CX-072 response. |
|
| E.3 | Principal inclusion criteria |
All pts must have histologically confirmed diagnosis of metastatic or locally advanced unresectable tumors that progressed or are intolerant to standard therapy.
-Part A:any metastatic or advanced unresectable solid tumor or lymphoma, measurable or nonmeasurable disease allowed, no further SOC therapy available;•Immunotherapy naive, including PD-1/PD-L1 and CTLA-4 inhibitor therapy naive
-Part A2:any metastatic or advanced unresectable solid tumor or lymphoma, measurable disease allowed, no further SOC therapy available;•TPS≥1% membranous staining based on the DAKO PD-L1 IH22C3 pharmDo•Immunotherapy naive,including PD-1/PD-L1&CTLA-4 inhibitor therapy naive•Agreement to participate in biomarker analysis&have tumor site that is safe to biopsy
-Part B1:any metastatic or advanced unresectable solid tumor or lymphoma, measurable or nonmeasurable disease allowed, no further SOC therapy available•Immunotherapy naive, including PD-1/PD- L1&CTLA-4 inhibitor therapy naïve -Part B2:any metastatic or advanced unresectable solid tumor or lymphoma with measurable disease allowed, no further SOC therapy available •Previous treatment with PD-1/PD-L1 inhibitor•Discontinued treatment with PD-1/PD-L1 inhibitor for reasons other than toxicity• Naive to treatment with CTLA-4 inhibitor•Agreement to participate in biomarker analysis and have tumor safe to biopsy -Part C:metastatic or advanced unresectable melanoma with BRAF V600E mutation-positive as detected by diagnostic approved test, measurable or nonmeasurable disease allowed •Naive to treatment with BRAF-inhibitor o Immunotherapy naive,including PD-1/PD-L1&CTLA-4 inhibitor therapy naïve -Part D:measurable disease is required•Must be willing to provide blood sample at Screening for hTMB testing•Immunotherapy naive,including PD-1/PD-L1&CTLA-4 inhibitor therapy naive(where there is no available life-prolonging immunotherapy or PD- 1/PD- L1&CTLA-4 inhibitor therapy to the pt)of the following tumor: UPS,small bowel adenocarcinoma,cSCC,MCC,Thymic carcinoma,Anal SCC,TNBC,hTMB - Part E:measurable disease is required•Must be willing to provide blood sample at screening for hTMB testing•Immunotherapy naive,including PD-1/PD-L1&CTLA-4 inhibitor therapy naive(where there is no available life-prolonging immunotherapy or PD-1/PD-L1&CTLA-4 inhibitor therapy available to the pts of following tumor: UPS,small bowel adenocarcinoma,cSCC,MCC,TET,Anal SCC,TNBC,TNBC with skin lesions For all A-E Parts:
1.Agreement to provide mandatory archival tissue/fresh biopsy. A tumor biopsy is required at baseline if there is no other record of histological diagnosis of tumor. 2.For pts in PartA2 and B2 (for PartB2, only those subjects receiving 3mg/kg of IPI)&those who agree to participate in biomarker analysis&who have tumor site that is safe to biopsy, pts must have biopsy within 90 days of study entry and be willing to undergo at least 1 on-treatment tumor biopsy. 3.Pts with treated brain metastases are eligible if brain metastases are stable and pt does not require radiation therapy,or steroids. Active screening for brain metastases (eg, brain CT or MRI) is not required 4.At least 18 years of age 5.ECOG performance status of 0 or 1 6. Anticipated life expectancy of at least 3 months. 7.Screening laboratory values must meet following criteria:
•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≥9.0g/dL or 90.0g/L
•Creatinine≤2mg/dL or 176.8μmol/L
•AST≤2.5×upper limit of normal (ULN); ≤5×ULN for pts with liver metastasis;<3×ULN for pts in PartC (VEM + CX-072).No upper limit for pts with HCC or pancreatic cancer
•ALT≤2.5×ULN; ≤5×ULN for pts with liver metastasis; <3×ULN for pts in Part C (vemurafenib+CX-072). No ULN for pts with HCC or pancreatic cancer
•Total bilirubin within ULN (unless diagnosed with Gilbert's syndrome, those patients must have a total bilirubin <3.0mg/dL or 51.3 μmol/L). No upper limit for pts with HCC
•Amylase and Lipase≤1.5 × ULN. No upper limit for pts with pancreatic cancer
8.Women of childbearing potential and males must agree to use highly effective method of contraception prior to study entry, while on study drug, and for period of 105 days following last treatment and for 180 days if receiving VEM 9.Ability to understand and willingness to sign written informed consent document and adhere to study schedule and prohibitions
For Long-term extension (LTE):
1.Previously participated in Study CTMX-M-072-001
2.Actively receiving CX-072 monotherapy;pts must be assessed by Inv as still receiving clinical benefit from CX-072 in Study without unacceptable toxicity
3.Demonstrated compliance as assessed by Inv during study
4.Women of childbearing potential and males must agree to use highly effective method of contraception prior to study entry,while taking study drug,& for a period of 105 days following last treatment
5.Written IC must be obtained prior to enrolling in LTE
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|
| E.4 | Principal exclusion criteria |
1. Prior therapy with a chimeric antigen receptor (CAR) T-cell containing regimen.
2. Baseline QTc is > 470 ms, or taking any medication known to prolong the QT interval.
3. Prior history of myocarditis irrespective of the cause.
4. Treatment with strong cytochrome P450 (CYP) 3A4 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 therapeutic.
6. Active or history of uveal, mucosal, or ocular melanoma is excluded in Parts B2 and C.
7. History of interstitial lung disease for patients with TET are excluded in Part B1 and B2.
8. Human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS)-related illness, acute or chronic hepatitis B or C; patients with HIV that have an undetectable viral load and a CD4 cell count > 400/mL and who remain on antiretroviral regimen will be eligible for enrollment into anal SCC cohorts in Parts D and E and hTMB cohort in Part D;
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, type 1 insulin dependent diabetes mellitus or myasthenia gravis.
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 or immunotherapy or any investigational treatment within 14 days prior to receiving study drug; radiation therapy within 3 months prior to receiving study medication (except for radiotherapy for the purposes of palliation confined to a single field that is not the target lesion).
13. Patients in Part C cannot have a glomerular filtration rate 60mL/min/1.73 m2;
14. 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.
15. Unresolved acute toxicity of the NCI CTCAE v4.03 Grade > 1 (or baseline, whichever is greater) that may put the patient at high risk under the current treatment. Alopecia and other non acute toxicities are acceptable.
16. 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.
17.Received a live vaccine within 30 days prior to first dose of study drug.
18. Known pre-existing condition of age-related macular degeneration.
19. Intercurrent illness, including, but not limited to symptomatic congestive heart failure (ie, New York Heart Association Class III or IV), unstable angina pectoris, clinically significant and uncontrolled cardiac arrhythmia, nonhealing wound or ulcer, or psychiatric illness/social situations that would limit compliance with study requirements.
20. Pleural effusion, pericardial effusion, or recurrent ascites drainage.
21. Ongoing or active infection (including fever within 48 hours of screening).
22. Participating in an ongoing clinical study involving treatment with medications, radiation or surgery.
23. Women who are pregnant or breastfeeding.
For Long-term extension:
1.Illness or medical condition which in the opinion of the investigator could compromise patient's safety at enrollment
2.Prohibited concomitant therapy outlined in the protocol
3.Concurrent participation in another therapeutic clinical trial
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|
| 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).
For Long-term extension:
1.The reason and date for discontinuation from treatment will be recorded on the eCRF. |
|
| 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 | 3 |
| 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 |
| 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
|
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| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | 18 |
| 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 | 9 |
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