| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Metastatic colorectal cancer
Advanced solid tumors |
|
| E.1.1.1 | Medical condition in easily understood language |
Colon cancer
Other solid tumors |
|
| 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 | 27.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10052358 |
| E.1.2 | Term | Colorectal cancer metastatic |
| 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 | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| 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 |
Dose escalation:
• To determine the RP2D of single-agent petosemtamab in mCRC
patients who have progressed on chemotherapy, with or without an
antivascular endothelial growth factor (VEGF) therapy, and with an anti-
EGFR therapy (if RASwt)
Dose expansion (single agent):
• To determine the ORR per RECIST 1.1 (per investigator)
Dose expansion (single agent, randomized expansion in HNSCC 2/3L):
• To descriptively characterize all relevant clinical safety and efficacy
data within the study
• To characterize the exposure-safety relationship of petosemtamab
administered at 1100 mg and 1500 mg Q2W in terms of TEAEs
Dose expansion (combination HNSCC 1L):
• To determine the overall response rate (ORR) per RECIST 1.1 (per
investigator review)
• To characterize safety and tolerability for combinations
Dose expansion (combination, 2L mCRC cohort)
• To characterize safety and tolerability for petosemtamab in
combination with FOLFIRI/FOLFOX |
|
| E.2.2 | Secondary objectives of the trial |
Dose escalation:
safety and tolerability
PK
immunogenicity
biomarkers in tumor samples relevant to EGFR and LGR5 and tumor response profile
antitumor activity
Dose exp. (single agent/combination):
antitumor activity in terms of PFS, DOR RECIST 1.1 (per investigator)
and in exp. cohorts with antitumor activity observed (per central review)
OS
safety/tolerability of single-agent peto. and confirm the RP2D
PK of peto. (single agent) and of peto. in combo with pembro /FOLFOX/FOLFIRI
immunogenicity of peto.
biomarkers relevant to EGFR and LGR5 and tumor response of peto.
Dose exp. (single agent, randomized exp. in HNSCC 2/3L):
exposure-efficacy relationship of peto. at 1100 mg and 1500 mg Q2W:
sum of lesions and in terms of Grade 3-4 TEAEs, IRRs and non-IRR TEAEs
other safety
PK
immunogenicity
antitumor activity: ORR, DOR, PFS RECIST 1.1 (per investigator/centralreview)
biomarkers in samples relevant to EGFR and LGR5 as well as the early
tumor response profile |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1 Signed ICF
2 Age ≥ 18 y
3. Histologically/cytologically confirmed solid tumors with evidence of
metastatic or locally advanced disease not amenable to standard therapy
with curative intent:
• Expansion cohorts: patients (pts) with locally advanced unresectable
or metastatic disease for the following indications:
oSINGLE AGENT
o2nd/3rd-LINE HNSCC PATIENTS: pts who have progressed on or after,
or are intolerant to, anti-PD-(L)1 therapy as monotherapy or in
combination , and have progressed to a Pt-based chemotherapy less
than 6 months from the last Pt dose, with no previous EGFR inhibitors.
Pts with no more than 2 prior lines of treatment in recurrent or
metastatic disease not amenable to standard therapy with curative
intent.
HPV status by p16 IHC or molecular HPV test for all oropharyngeal
tumors should be reported when available.
The eligible HNSCC primary tumor locations are oropharynx, oral cavity,
hypopharynx, and larynx.
oCancers of the anogenital tract with squamous cell histology
oSkin SCC
oNSCLC non-SCC and SCC
oGEA with histologically confirmed EGFR amplification FISH score
EGFR/CEP7 ratio ≥2.0, or NGS EGFR copy ≥8, or cfDNA ≥2.5, or EGFR
IHC H-score ≥200)
oPA
o mCRC in 3L+. Patients should be free of mutations in RAS, KRAS,
NRAS, HRAS, RAF, BRAF, ARAF, RAF1,
If the patient was treated with an EGFR inhibitor in 1L or 2L, then the
patient should have shown CR)/PR and should have at least 6 months of
interval since the last administration of EGFR inhibitor.
oCOMBINATION
o1st HNSCC: pts eligible to receive pembro. as 1st-line monotherapy
with tumors expressing PD-L1, CPS ≥1; pts should not have previous
systemic therapy in the
recurrent or metastatic setting, although previous systemic therapy as
part of multimodal treatment for locally advanced disease is allowed if
ended ≥6 months prior to signing the ICF. The eligible HNSCC primary
tumor locations are oropharynx, oral cavity, hypopharynx, and larynx.
Previous treatments with anti-PD-(L)1 or anti-EGFR therapies are not
allowed
2L mCRC: Patients should have been previously diagnosed with
histologically or cytologically confirmed unresectable or metastatic
adenocarcinoma of the CRC. Patients must be RAS/RAF WT . Patients
must be naive to prior anti-EGFR . Radiographically confirmed disease
progression must have occurred within 6 months of prior 1L.
o Cohort petosemtamab and FOLFIRI: patients should have had only 1
prior chemotherapy regimen for the metastatic setting, consisting of 1L
fluoropyrimidine-oxaliplatin-based chemotherapy ± bevacizumab. Note:
FOLFOX-based adjuvant treatment would be considered front-line if PD
occurred within 6 months of completion of adjuvant therapy.
o Cohort petosemtamab and FOLFOX: patients should have had only 1
prior chemotherapy regimen for the metastatic setting, consisting of 1L
fluoropyrimidine-irinotecan-based chemotherapy ± bevacizumab.
4. A baseline new tumor sample FFPE from a metastatic or primary site.
If the pt has an available tumor sample as an FFPE block with sufficient
material and has not received further anticancer treatment since sample
collection, a new tumor biopsy at baseline is not necessary. Archival
FFPE slides are not acceptable.Archival
tumor material is only acceptable if the patient has not
been treated with anti-EGFR or anti-human epidermal growth factor
receptor (HER)-2 therapies.
5 Amenable for biopsy
6 Measurable disease per RECIST 1.1
7.ECOG PS 0-1
8.Life expectancy ≥ 12 weeks
9.LVEF ≥ 50% by ECHO/MUGA
10 Adequate organ function:
•ANC ≥1.5 X 109/L
•Hb ≥9 g/dL
•Platelets ≥100 x 109/L
•Serum Mg cCa, K, Na and phosphate within normal ranges (or corrected
with supplements)
•ALT, AST ≤2.5xULN and total bilirubin ≤1.5xULN (unless due to known
Gilbert's syndrome who are excluded if total bilirubin >3.0xULN or direct
bilirubin >1.5xULN); in cases of liver involvement, ALT/AST ≤5xULN and
total bilirubin ≤2xULN will be allowed, unless due to known Gilbert's
syndrome when total bilirubin ≤3.0xULN or direct bilirubin ≤1.5xULN
will be allowed or hepatocellular carcinoma [Child-Pugh class A] when
total bilirubin <3 mg/dL will be allowed.
•Serum creatinine ≤1.5xULN or creatinine clearance ≥60 mL/min
calculated according to the Cockroft and Gault formula or MDRD formula
for pts aged >65 years
•Serum albumin ≥3 g/dL
•INR/PT ≤1.5xULN unless pts is receiving anticoagulant therapy and in
therapeutic range of intended used anticoagulant.
•APTT/PTT≤1.5xULN unless pts is receiving anticoagulant therapy and
is in therapeutic range of intended used anticoagulant
11 Willing to undergo testing for HIV if not tested within the past 6
months. HIV-positive ptsare eligible provided the CD4+ count is ≥
300/μL, viral load is undetectable, and the pt is currently receiving |
|
| E.4 | Principal exclusion criteria |
1. CNSmetastases that are untreated or
symptomatic, or require radiation, surgery, or continued steroid therapy
to control symptoms within 14 days of study entry.
2. Known leptomeningeal involvement
3. Participation in another CT or treatment with any
investigational drug within 4 weeks prior to study entry
4. Any systemic anticancer therapy within 4 weeks or 5 half-lives,
whichever is shorter, of the first dose of study treatment. For cytotoxic
agents that have major delayed toxicity (eg, mitomycin C, nitrosoureas),
or anticancer immunotherapies, a washout period of 6 weeks is required.
5. Requirement for immunosuppressive medication
6. Major surgery or radiotherapy within 3 weeks of the first dose of
study treatment. Patients who received prior radiotherapy to ≥25% of
bone marrow are not eligible, irrespective of when it was received.
7. Persistent Grade >1 clinically significant toxicities related to prior
antineoplastic therapies (except for alopecia); stable sensory
neuropathy Grade ≤2 v4.03 is allowed.
8. History of hypersensitivity reaction to any of the excipients of
petosemtamab, human proteins, or any non-IMP treatment required for
this study
9. Uncontrolled hypertension (systolic [BP] >150 mmHg
and/or diastolic BP >100 mmHg) with appropriate treatment; unstable
angina; history of congestive heart failure of Class II-IV New York Heart
Association (NYHA) criteria, or serious cardiac arrhythmia requiring
treatment (except atrial fibrillation, paroxysmal supraventricular
tachycardia); or history of myocardial infarction within 6 months of
study entry
10. History of prior malignancies with the exception of excised cervical
intraepithelial neoplasia or nonmelanoma skin cancer, or curatively
treated cancer deemed at low risk for recurrence with no evidence of
disease for ≥3 years.
11. Current dyspnea at rest of any origin, or other diseases requiring
continuous oxygen therapy, including patients with a history of
interstitial lung disease (ILD) (eg, pneumonitis or pulmonary fibrosis),
or evidence of ILD on baseline chest computerized tomography (CT)
scan
12. Current serious illness or medical conditions including, but not
limited to, uncontrolled active infection, clinically significant pulmonary,
metabolic, or psychiatric disorders
13. Patients with known infectious diseases:
• Active hepatitis B infection without receiving antiviral treatment. Note:
o Patients who are HbsAg positive must receive antiviral treatment with
lamivudine, tenofovir, entecavir, or other antiviral agents, starting at
least ≥7 days before the initiation of study treatment.
o Patients with antecedents of hepatitis B (eg, anti-hepatitis B core
(anti-HBc) positive, HbsAg, and hepatitis B virus [HBV] DNA negative)
are eligible.
• Positive test for hepatitis C virus (HCV) RNA. Note: Patients in whom
HCV infection resolved spontaneously (ie, positive HCV antibodies
without detectable HCV RNA), or who achieved a sustained response
after antiviral treatment and show absence of detectable HCV RNA ≥6
months (with the use of interferon [IFN]-free regimens) or ≥12 months
(with the use of IFN-based regimens) after cessation of antiviral
treatment, are eligible.
14. Pregnant or breastfeeding patients; patients of childbearing potential
must use highly effective contraception methods prior to study entry, for
the duration of study participation, and for 6 months after the last dose
of petosemtamab.
15. 1L HNSCC combination cohort: has a diagnosis of immunodeficiency,
or is receiving systemic steroid therapy or any form of immunosuppressive therapy within 7 days prior to the first dose.
Corticosteroids used as premedication for allergic reactions or IRRs
specified in the protocol are allowed.
16. 1L HNSCC combination cohort: active autoimmune disease that has
required systemic immune suppressive treatment in the past 2 years;
replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not
considered immune suppressive treatment.
17. 1L HNSCC combination cohort: has had an allogeneic tissue/solid
organ transplant
18. 1L HNSCC combination or HNSCC single-agent cohort: patients may
not have a primary tumor site of nasopharynx (any histology).
19. Patients previously treated with anti-EGFR inhibitors are not eligible
for this study (except in 3L+ mCRC, see Inclusion Criterion [IC] 3).
20. mCRC cohorts: mCRC with a RAS/RAF mutation identified by local
ctDNA or tumor test at screening, or identified as such in disease history,
are not eligible for this study.
21. 2L mCRC cohorts: Patients with an active inflammatory bowel
disease, or other bowel disease causing chronic diarrhea (defined as
NCI-CTCAE Grade ≥2), are not eligible for this study.
22. 2L mCRC cohorts: Patients with peripheral sensory neuropathy with
functional impairment (Grade ≥3) are not eligible for this study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Escalation:
- Incidence and severity of DLTs during Cycle 1
Expansion (single agent non randomized:
- ORR, per RECIST 1.1 (per investigator review)
Expansion Combination HNSCC 1L
- ORR, per RECIST v1.1 as assessed by investigator review
- Incidence, severity, and relationship of AEs and SAEs, in combination
with pembrolizumab in HNSCC
Expansion Combination mCRC 2L
- Incidence, severity, and relationship of AEs and SAEs, in combination
with FOLFIRI/FOLFOX in 2L mCRC
Dose expansion (single-agent, randomized expansion in 2L/3L HNSCC
cohort)
• Incidence, severity, and relationship of AEs and SAEs
• Treatment discontinuations due to AEs and dose modifications due to
AEs
• BOR |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Escalation: during cycle 1
Expansion: during treatment |
|
| E.5.2 | Secondary end point(s) |
Escalation:
• Incidence, severity, and relationship of adverse events (AEs) and
serious adverse events (SAEs); incidence, severity and changes in
laboratory values; measures and changes in electrocardiogram (ECG)
and vital signs
• Treatment discontinuations due to AEs and dose modifications due to
AEs
• Best overall response per Response Evaluation Criteria in Solid Tumors
Guidelines (RECIST) 1.1 (per investigator review)
• Concentration at end of infusion (CEOI), maximum drug concentration
(Cmax), C0h, area under curve (AUC), clearance (CL), volume of
distribution at steady state (Vss), time of observed maximum serum
drug concentration (tmax) and terminal half-life (t1/2), and a
population PK analysis
• Incidence and serum titers of antidrug antibodies (ADAs) against
petosemtamab
• Cytokine panel expression profile
• EGFR and LGR5 expression
Expansion (single agent and combination):
• PFS, per RECIST 1.1 (per investigator review)
• DOR, per RECIST 1.1 (per investigator review)
• ORR, per RECIST 1.1 (per central review)
• DOR, per RECIST 1.1 (per central review)
• OS
• Incidence, severity, and relationship of AEs and SAEs; incidence,
severity and changes in laboratory values; measures and changes in ECG
and vital signs
• Treatment discontinuations due to AEs and dose modifications due to
AEs
• CEOI, Cmax, C0h, AUC, CL, Vss, tmax and t1/2, and a population PK
analysis
• Incidence and serum titers of ADAs against petosemtamab
• Cytokine panel expression profile
• EGFR and LGR5 expression
• Biomarkers for resistance or response to EGFR therapies, EGFR and
WNT signaling molecules, plasma proteins, genetic aberrations in DNA of
tumor tissue or ctDNA, expression of m(i)RNA and tumor immune
phenotype
• PD biomarkers for molecular and physiological response on treatment
• Insight into mechanism of action, including response and potential
toxicity
• Percentage change from baseline in sum of the diameters of target
lesions at Week 8
• Incidence of Grades 3-4 TEAEs at Week 8
• Incidence of IRR TEAEs at Week 8
• Incidence of non-IRR TEAEs at Week 8
• PFS rate at 4 months, per RECIST v1.1 as assessed by investigator
review |
|
| 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 | 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 | No |
| 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 | Yes |
| 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.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Belgium |
| France |
| Italy |
| Netherlands |
| Portugal |
| Spain |
|
| 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 | 9 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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