| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Metastatic or locally advanced unresectable solid tumors in following
indications: breast cancer (BC), castrate-resistant prostate
carcinoma (CRPC), non-small cell lung carcinoma (NSCLC), ovarian epithelial
cancer (EOC), endometrial carcinoma (EC), head and neck squamous
cell carcinoma (HNSCC), or cholangiocellular carcinoma (CCC) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
PartA determine safety of CX2009, MTD/RP2D/DLTs of CX2009 given IV
every 21d as monotherapy to pts with solid tumors.
PartA2:characterize protease activity+measure cleavage of CX2009 in
biopsies,blood in pts with high CD166 by IHC, obtain characterization of
safety of CX2009 given as monotherapy.
PartB:evaluate efficacy of CX2009 given IV every 21d as monotherapy at
MTD/RP2D in pts with solid tumors (high CD166 by IHC).
PartC1:determine safety of CX2009,MTD/RP2D/DLTs of CX2009 given IV
every 14d as monotherapy to pts with solid tumors (high CD166 by IHC)
PartC2:evaluate clinical activity of CX2009 given IV every 14d as
monotherapy at MTD/RP2D to pts in an indication specific cohort high
CD166 by IHC.
Part D1:determine safety,MTD/RP2D/DLT's of CX2009 in comb with
CX072 both given IV every 14d
Part D2 evaluate efficacy of CX2009 in comb. with CX072 given IV every
14d at MTD/R2PD to subjects PDL1+ and high CD166 by IHC. |
|
| E.2.2 | Secondary objectives of the trial |
Evaluate preliminary efficacy in subjects treated with CX-2009 as monotherapy;
Characterize the pharmacokinetics (PK) of CX-2009;
Assess the incidence of anti-drug antibody (ADA) formation to CX-2009;
Obtain additional characterization of the safety of CX-2009 at the MTD/RP2D;
Evaluate efficacy in subjects treated with CX-2009 as monotherapy.
Evaluate preliminary efficacy in subjects treated with CX-2009 and CX-072
Characterize PK of CX-2009 when administered in combination with CX-072
Assess incidence of ADA formation to CX-2009 when it's administered in
combination with CX-072
Characterize the PK profile of CX-072 when it's administered in
combination with CX-2009
Assess the incidence to ADA formation to CX-072 when it's administered
with CX-2009
Obtain additional characterization of safety of CX-2009 when
administered with CX-072 at MTD/RP2D
Evaluate Efficacy of CX-2009 + CX072 |
|
| 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 |
Substudy protocol title: 89Zr-CX-2009 PET Imaging in Subjects with Unresectable Locally Advanced or Metastatic Solid Tumors
Protocol Module Number: PROCLAIM CTMX-M-2009-001 substudy
The primary objective of the substudy is to assess the whole body distribution of 89Zr-CX-2009, including the uptake (visual and quantitative) in tumor lesions as well as non-tumor tissues, in subjects with unresectable locally advanced or metastatic solid tumors.
The secondary objectives of the substudy are:
1.To evaluate the safety of 89Zr-CX-2009;
2.To evaluate the dosimetry of 89Zr-CX-2009;
3.To evaluate the correlation of 89Zr-CX-2009 tumor uptake with CD166 expression as assessed in archival tumor sample and/or fresh tumor biopsy;
4.To assess the heterogeneity of 89Zr CX 2009 tumor uptake within and between subjects;
5.To characterize the PK profile of CX-2009 with respect to the following analytes:
•Intact CX-2009 (referring to the prodrug form of CX-2009 ± DM4);
•Total CX-2009 (intact and activated forms of CX-2009 ± DM4);
•Total CX-2009-conjugated DM4 (antibody conjugated-DM4);
•Free DM4;
•S-methyl DM4 (DM4-Me) - a DM4 metabolite with potent cytotoxic activity.
6. To characterize the PK profile of 89Zr-CX-2009.
The exploratory objectives of the substudy are:
1.To evaluate the correlation between tumor uptake of 89Zr-CX-2009 and response to therapy on lesions level and on subject level;
2.To characterize the CD166 expression, protease activity, and activation of CX-2009 in on-treatment tumor biopsies and peripheral blood, respectively.
This substudy will only be conducted in the VUMC (The Netherlands) |
|
| E.3 | Principal inclusion criteria |
1. Histologically confirmed diagnosis of active metastatic or locally
advanced unresectable solid tumor in subjects who have disease
progression after treatment with available therapies that are known to
confer clinical benefit, or who are intolerant to treatment in following
indications:
Eligible indications, by Part:
Part A: BC, CRPC, NSCLC (including adenocarcinoma and squamous cell
subtypes), OEC, EC, HNSCC, and CCC;
Part A2: BC, NSCLC (including adenocarcinoma and squamous cell
subtypes), OEC,EC, and HNSCC;
Parts B, C2, and D2: TNBC, hormone receptor (HR; ie, estrogen and/or
progesterone)-positive/HER2-negative BC, NSCLC (including
adenocarcinoma and squamous cell subtypes), OEC, and HNSCC; and
Parts A mTPI-2 cohort, C1, and D1: BC, NSCLC (including
adenocarcinoma and squamous cell subtypes), and HNSCC;
Criterion specific to Parts B, C, and D:
Subjects must have received the standard prior treatments for
metastatic or advanced unresectable disease as outlined below, but not
more than 3 (≤3) prior lines in total;
2. Agrees to provide tumor tissue, archival, new or recent acquisition
confirmed to be available prior to initiation of study drug for
performance of correlative tissue and cellular studies from a tumor site
not previously irradiated
3. Evaluable or measurable disease required for dose escalation (Part A)
and measurable disease per RECIST v1.1 required for Parts A2, B, C1, C2,
D1 and D2
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 or magnetic resonance imaging) is not required;
5. At least 18 years of age;
6. Eastern Cooperative Oncology Group performance status of 0 or 1;
7. Anticipated life expectancy of at least 3 months;
8. screening lab values must meet following criteria: absolute neutrophil
count >=1500μl; platelet count >= 100 x 10³/μl (must not have been
transfused within prev. 10 days); hemoglobin >=9.0 g/dL (may have
been transfused); serum creatinine <= 1.5 x institution upper limit of
normal (ULN); aspartate aminotransferase (AST) <= 2.5xinstitution's
ULN; alanine aminotransferase (ALT) <= 2.5x institution's ULN (AST,
ALT <5 x ULN for subjects with CCC and liver metastases); and serum
total bilirubin <= 1.5x institutional ULN (total bilirubin must be <=3x
institution's ULN in subjects with Gilbert's syndrome). Serum total
bilirubin <= 3.0 x institutional ULN for subjects with CCC and liver
metastasis
For Parts B, C, D only: Hemoglobin >= 9.0 g/dL (without transfusion
within 30 days of Cycle 1
Day 1); AST, ALT, and alkaline phosphatase (ALP) <=2.5 × institution's
ULN (without exemption for liver or bone metastases); International
normalized ratio (INR) and activated partial thromboplastin time
(aPTT) <= 1.5 × ULN (unless subject is on therapeutic anticoagulation,
at which time the INR and aPTT must be in the target therapeutic
anticoagulation range); and Serum albumin >=2.5 g/dL.
9. Women of childbearing potential (defined as women who have
experienced menarche and who are not permanently sterile or
postmenopausal; postmenopausal is defined as 12 consecutive months
with no menses without an alternative medical cause), and males must
agree to use a highly effective method of contraception prior to study
entry, while on study drug and for a period of 50 days after the last dose
of CX2009 or 6 months after the last dose of CX072 whichever is later;
highly effective methods of contraception which result in a low failure
rate (ie <1 % per year) when used consistently and correctly include
implants, injectables, combined hormonal contraceptives, some IUD's,
sexual abstinence or a vasectomized partner - True abstinence, when
in line with the preferred and usual lifestyme of the subjects is
considered a highly effective method only if defined as refraining from
heterosexual intercourse during the entire period of risk associated with
the study treatments. (periodic abstinence and withdrawal are not
acceptable methods of contraception)
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. Neuropathie > grade 1
2. Active chronic corneal disorder, including but not limited to the following: sjogren's syndrome, Fuchs corneal dystropathy (requiring treatment), history of corneal transplantation, active herpetic keratitis, and also active ocular conditions requiring ongoing treatment/monitoring such as wet age-related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular edema, presensce of papilledema and acquired monocular vision
3. Serious concurrent illness, including, but not limited to following:
- clinically relevant active infection including known active hepatitis B or C. HIV infection or CMV infection or any other known concurrent infectious disease requiring IV antibiotic, antiviral or antifungal therapy within 2 weeks of study enrollment
- history of or current active autoimmune diseases, including but not limited to myasthenia gravis, inflammatory bowel diseases, RA, autoimmune thyroiditis which is not a sequela of prior immune checkpoint therapy, autoimmune hepatitis, systemic sclerosis, systemic lupus erythematosus, autoimmune vasculitis, autoimmune neuropathies or type 1 insuline dependent diabetes mellitus
- significant cardiac disease such as recent MI (<= 6 months prior to day 1), unstable angina pectoris, uncontrolled congestive heart failure (NY Heart association >class II), uncontrolled hypertension (NCI CTCAE v.4.03 grade 3 or higher), uncontrolled cardiac arrythmias, severe aortic stenosis or >= grade 3 cardiac toxicity following prior chemotherapy
- History of multiple sclerosis or other demyelinating disease, Eaton-Lambert syndrome (para-neoplastic syndrome), history of hemorrhagic or ischemic stroke within the last 6 months, or alcoholic liver disease
- Non-healing wound(s) or ulcer(s) except for ulcerative lesions caused by the underlying neoplasm
- Psychiatric illness/social situations that would limit compliance with study requirements
- Interstitial lung disease irrespective of etiology
4. Advanced or metastatic Stage IV NSCLC subjects with EGFR or ALK genomic alterations unless they have progressed on treatment with appropriate targeted therapy, including osimertinib for T790M mutation-positive NSCLC
5. Any other anti-cancer treatment such as chemotherapy, immunotherapy, biochemotherapy, radiotherapy, investigative therapy, or high-dose steroids within 30 days of receiving study drug. Low-dose steroids, luteinizing hormone-releasing hormone, aromatase inhibitors (eg, anastrozole), at doses that have been stable for 30 days are permitted for subjects with CRPC
6. History of severe allergic or anaphylactic reactions to previous mAb therapy
7. Prior treatment with maytansinoid-containing drug conjugates
8. Subjects with a previously documented absence of thiol-S-purine methyltransferase activity
9. Unresolved acute toxicity NCI CTCAE v4.03 Grade >1 (or baseline, whichever is greater) from prior anti-cancer therapy. Alopecia and other non-acute toxicities are acceptable
10. 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, are considered to have been cured and in the opinion of the Investigator, present a low risk for recurrence, including basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the prostate, cervix or breast
11. Currently receiving anticoagulation therapy with warfarin
12. The subject has undergone major surgery (requiring general anesthesia) within 3 months prior to dosing. Subjects who have undergone major surgery within this time period may be enrolled, after consultation with the medical monitor
13. Subjects who have received a live vaccine 28 days prior to the planned first dose of CX-2009
14. Participating in an ongoing clinical study involving treatment with medications, radiation, or surgery
15. Women who are pregnant or breast feeding
16. Subjects who are >20% below their ideal body weight
FOR PART D1 AND D2
17. History of myocarditis regardless of the cause;
18. History of intolerance to prior ICI therapy defined as the need to
discontinue treatment due to an irAE;
19. History of any syndrome or medical condition that requires
treatment with systemic steroids
(≥10 mg daily prednisone equivalents) or immunosuppressive
medications. However,
subjects who require brief courses of steroids (eg, as prophylaxis for IV
contrast or for
treatment of an allergic reaction) may be eligible with Sponsor approval.
Inhaled or topical
steroids are permitted;
20. History of allogeneic tissue/solid organ transplant, stem cell
transplant, or bone marrow
transplant. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Dose-limiting toxicities
Study-drug related AEs and AEs leading to discontinuation
Changes from baseline in clinical laboratory results and vital signs |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Administrative interim analyses on safety and efficacy or on PK, immunogenicity, and selected biomarkers may be performed at several times prior to completion of the study in order to facilitate program decisions and to support study presentations or publications
|
|
| E.5.2 | Secondary end point(s) |
Part A
The secondary objectives of Part A are:
•Evaluate preliminary efficacy in subjects treated with CX-2009 as
monotherapy on the basis of:
ORR by the RECIST Version 1.1, Time to tumor response (TTR), Duration
of response (DOR), Progression-free survival (PFS), Overall survival
(OS)
•Characterize PK of CX-2009 with respect to the following analytes:
- Intact CX-2009 (referring to the prodrug form of CX-2009 DM4)
- Total CX-2009 (intact and activated forms of CX-2009 DM4)
- Total CX-2009-conjugated DM4 (antibody conjugated-DM4)
- Free DM4
- S-methyl DM4 (DM4-Me), a DM4 metabolite with potent cytotoxic
activity;
•Assess the incidence of ADA formation to CX-2009
Part A2
The secondary objectives of Part A2 are to determine:
•Evaluate preliminary efficacy in subjects treated with CX-2009 as
monotherapy on the basis of:
- ORR by the RECIST Version 1.1; TTR; DOR; PFS; and OS
•Characterize the PK of CX-2009 with respect to the following analytes:
- Intact CX-2009
- Total CX-2009
- Total CX-2009-conjugated DM4
- Free DM4
- DM4-Me
•Assess the incidence of ADA formation to CX-2009
Part B
The secondary objectives of Part B are to:
•Obtain additional characterization of the safety of CX-2009 at the
MTD/RP2D
•Evaluate efficacy in subjects treated with CX-2009 as monotherapy on
the basis of:
- DOR; TTR; PFS; and OS
•Characterize the PK of CX-2009 with respect to the following analytes:
- Intact CX-2009
- Total CX-2009
- Total CX-2009-conjugated DM4
- Free DM4
- DM4-Me
•Assess the incidence of ADA formation to CX-2009
Part C1
The secondary objectives of Part C1 are
•Evaluate preliminary clinical activity in subjects treated with CX-2009
as monotherapy on the basis of:
- ORR by the RECIST Version 1.1;TTR; DOR; PFS; and OS;
•Characterize the PK of CX-2009 with respect to the following analytes:
- Intact CX-2009
- Total CX-2009
- Total CX-2009-conjugated DM4
- Free DM4
- DM4-Me
•Assess the incidence of ADA formation to CX-2009
Part C2
The secondary objectives of Part C2 are to:
•Obtain additional characterization of the safety of CX-2009 at the
MTD/RP2D
•Evaluate clinical activity in subjects treated with CX-2009 as
monotherapy on the basis of:
- DOR;TTR;PFS; and OS;
•Characterize the PK of CX-2009 with respect to the following analytes:
- Intact CX-2009
- Total CX-2009
- Total CX-2009-conjugated DM4
- Free DM4; and
- DM4-Me; and
•Assess the incidence of ADA formation to CX-2009.
Part D1
The secondary objectives of Part D1 are to determine
•Evaluate preliminary efficacy in subjects treated with CX-2009 plus CX-
072 on the basis of: ORR by the RECIST Version 1.1; ORR by immunerelated
RECIST (irRECIST) as defined in the Core; TTR;DOR;PFS;OS;
•Characterize PK of CX-2009 when it is administered in combination with
CX-072:
- Intact CX-2009
- Total CX-2009
- Total CX-2009-conjugated DM4
- Free DM4
- DM4-Me
•Assess the incidence of ADA formation to CX-2009 when it is
administered in combination with
CX-072
• Characterize the PK profile of CX-072 when it is administered in
combination with CX-2009
•Assess the incidence of ADA formation to CX-072 when it is
administered in combination with CX-
2009
Part D2
The secondary objectives of Part D2 are:
• Obtain additional characterization of the safety of CX-2009
administered with CX-072 at the
MTD/RP2D;
• Evaluate efficacy in subjects treated with CX-2009 plus CX-072 on the
basis of: DOR;TTR;PFS; and OS;
• Characterize the PK of CX-2009 when it is administered in combination
with CX-072 with respect to
the following analytes:
-Intact CX-2009
-Total CX-2009
-Total CX-2009-conjugated DM4
-Free DM4
-DM4-Me
• Assess the incidence of ADA formation to CX-2009 when it is
administered in combination with
CX-072
• Characterize the PK profile of CX-072 when it is administered in
combination with CX-2009
• Assess the incidence of ADA formation to CX-072 when it is
administered in combination with
CX-2009 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Administrative interim analyses on safety and efficacy or on PK, immunogenicity, and selected biomarkers may be performed at several times prior to completion of the study in order to facilitate program decisions and to support study presentations or publications
|
|
| 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 | No |
| 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 | 1 |
| 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 | 16 |
| 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 |
| Germany |
| Netherlands |
| Spain |
| 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 | 6 |
| 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 | 6 |
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