A Phase 1-2, Open-Label, Dose-Finding, Proof of Concept, First-in-Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CX-2009 in Adults with Metastatic or Locally Advanced Unresectable Solid Tumors
- Conditions
- Metastatic or Locally Advanced Unresectable Solid Tumors10027476
- Registration Number
- NL-OMON48575
- Lead Sponsor
- CytomX Therapeutics, Inc.
- Brief Summary
Trial ended prematurely
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 22
Subjects who fulfill the following criteria at Screening will be eligible for
admission into the
study:
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 the following
indications (with guidance for standard treatment below).
For Parts A2, B, C1, C2, D1, and D2, an archival tumor tissue sample must be
submitted to
the central laboratory for evaluation of CD166 expression and demonstrate
confirmed high
CD166 expression by IHC. Biopsy collection for the purpose of determining
eligibility is not
permitted.
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;
Standard prior treatments, by tumor type:
BC (Parts A, A2, C1, and D1):
* Patients with HER2-positive BC are required to have progressed on
HER2-targeted
therapy (trastuzumab, pertuzumab, and/or T-DM1);
* Estrogen-receptor-positive should have received anti-hormonal therapy, a
CDK4/6
inhibitor, or mTOR inhibitor and progressed; and
* TNBC should have received at least 2 prior lines of therapy;
TNBC (Parts B, C2, and D2):
* Should have received at least 2 prior lines of therapy; and
* Subjects with BReast CAncer gene (BRCA) mutations must be refractory to or
otherwise ineligible for poly adenosine diphosphate-ribose polymerase
inhibitors (eg,
olaparib), if approved and available;
HR-positive/HER2-negative BC (Parts B, C2, and D2):
* Should have received and progressed on an anti-hormonal therapy, targeted
therapy
(CDK4/6 or mTOR inhibitor), or chemotherapy;
* Endocrine refractory should have received at least 3 prior hormonal therapies
and
progressed;
* Post or pre-menopausal subjects receiving ovarian ablation or suppression
must have
progressed on an aromatase inhibitor (AI) in combination with a CDK4/6
inhibitor or
fulvestrant in combination with a CDK4/6 inhibitor; and
* Subjects who progressed within 12 months or while on a non-steroidal AI, must
have
progressed on an mTOR inhibitor and on a combination of exemestane with
everolimus (mTOR);
CRPC (Part A):
* Received at least 1 prior therapy (eg, abiraterone + prednisone, or
docetaxel + prednisone, or enzalutamide);
NSCLC, including adenocarcinoma and squamous cell
subtypes (All Parts):
* Should have received at least 1 platinum-containing regimen. as well as an
anti-PD-1
or anti-PD-L1 therapy; and an ICI should have been
administered if approved and available for the subject*s indi
Subjects who fulfill any of the following criteria at Screening will not be
eligible for admission:
1. Neuropathy >Grade 1;
2. Active or chronic corneal disorder, including but not limited to the
following: Sjogren's syndrome, Fuchs corneal dystrophy (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, presence of papilledema, and acquired
monocular vision;
3. Serious concurrent illness, including, but not limited to the following:
• Clinically relevant active infection including known active hepatitis B or
C, human immunodeficiency virus infection, or cytomegalovirus 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, rheumatoid
arthritis, 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
insulin dependent diabetes mellitus;
• Significant cardiac disease such as recent myocardial infarction (£6
months prior to
Day 1), unstable angina pectoris, uncontrolled congestive heart failure (New
York Heart Association >class II), uncontrolled hypertension (NCI CTCAE v4.03
Grade 3 or higher), uncontrolled cardiac arrhythmias, severe aortic stenosis,
or ³Grade 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;
or
• 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 anticancer 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 ³30 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 (eg, Kadcyla
[T-DM1]);
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 anticancer therapy. Alopecia and other nonacute toxicities are
acceptable;
10. History of malignanc
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>The primary criteria for defining evidence of anti-cancer activity and also for<br /><br>management of subject care will be a clinical response as defined by RECIST<br /><br>(Version 1.1). Efficacy in subjects treated with the combination CX-2009 plus<br /><br>CX-072 (Parts D1 and D2) will be explored additionally on the basis of ORR by<br /><br>irRECIST as defined in the Core (Appendix A). Management of subjects in Parts<br /><br>D1 and D2 may take into consideration tumor response assessed by irRECIST.<br /><br><br /><br>Substudy:<br /><br>Parameters which will be evaluated in the substudy are as follows:<br /><br>- Uptake of 89Zr-CX-2009 in tumor lesions;<br /><br>- Biodistribution of 89Zr-CX-2009 in normal tissues; and<br /><br>- Dosimetry.</p><br>
- Secondary Outcome Measures
Name Time Method <p>Concentration versus time data will be tabulated and plotted for the individual<br /><br>and mean CX-2009 (total and intact), CX-2009 conjugated DM4, and free DM4,<br /><br>including DM4-Me analytes and for total and intact CX-072 moieties.<br /><br><br /><br>Serum samples will be collected to assess the immunogenicity of CX-2009 Serum<br /><br>samples will be collected to assess the immunogenicity of CX-2009 and CX-072,<br /><br>the latter for Parts D1 and D2 only. Samples will be initially screened for<br /><br>ADAs.<br /><br><br /><br>The overall goal of the biomarker portion of CTMX-M-2009-001 is to explore A)<br /><br>Probody mechanistic proof of concept, and B) potential predictive markers<br /><br>associated with the clinical activity of CX-2009 alone or in combination with<br /><br>CX-072. </p><br>