*To evaluate the safety and tolerability of RO7009789 and vanucizumab when administered in combination* To determine the maximum tolerated dose (MTD) (for the SC administration and potentially for the IV), route and recommended Phase II dose of…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
solide tumoren
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety is the primary endpoint and all efficacy endpoints are secondary. Among
the efficacy endpoints, for the evaluation of the preliminary antitumor
activity of RO7009789 in combination with vanucizumab/bevacizumab, best ORR,
objective response rate, DCR, PFS, and OS (if data is mature at the time of
analysis) according to RECIST v1.1 will be considered primary.
Secondary outcome
Best ORR, objective response rate, DCR, and PFS will also be assessed according
to irRC and will be considered secondary.
Background summary
Lack of immune cell infiltration in the majority of solid tumors is seen as a
major barrier to the success of immunotherapy. Anti-angiogenic therapies such
as bevacizumab and vanucizumab are thought to exert anti-tumor effects at least
partly through normalization of tumor neovasculature, which could enhance tumor
infiltration of immune cells stimulated by immunotherapy. In addition, there is
substantial overlap between cell types and factors involved in immune
suppression in the tumor microenvironment and the regulation of
neovascularization. Thus, in the context of a RO7009789/vanucizumab
combination, immune suppression and angiogenesis are considered to be related
processes.
Study objective
*To evaluate the safety and tolerability of RO7009789 and vanucizumab when
administered in combination
* To determine the maximum tolerated dose (MTD) (for the SC administration and
potentially for the IV), route and recommended Phase II dose of RO7009789 when
administered in combination with vanucizumab
Part I (Dose Escalation):
* To characterize the pharmacokinetic (PK) and pharmacodynamics (PD) effects of
RO7009789 and vanucizumab when administered in combination
* To assess the biomarkers that might act as PD indicators of the immune
modulatory effect and anti-tumor activity of RO7009789 alone and in combination
with vanucizumab
* To evaluate the incidence of anti-drug antibodies (ADAs) against RO7009789
and vanucizumab and to assess their potential relationship with other outcome
measures
Part II (Expansion Cohorts):
* To evaluate the clinical activity of RO7009789 when administered in
combination with bevacizumab in patients with aPROC, HNSCC and NSCLC
* To evaluate the safety and tolerability of the combination RO7009789 and
bevacizumab
Study design
This is a Phase Ib, open-label, multicenter, global study designed to assess
the safety, tolerability and clinical activity of RO7009789 in combination with
vanucizumab in patients with metastatic solid tumors (except prostate cancer
and squamous non-small cell lung cancer [NSCLC]) that are not amenable to
standard treatment. This study consists of two parts: The aim of Part I is to
define the MTD for the SC route of administration (and potentially IV if
injection site reactions are dose limiting when administered SC) and the RP2D
of RO7009789 in combination with vanucizumab. Part II intends to investigate
the clinical activity of RO7009789 in combination with bevacizumab in defined
cancer types
Intervention
In Part I, cohorts of three patients will receive escalating doses of RO7009789
subcutaneously/intravenously every 28 days (Q4W) on Day 2 of Cycles 1 through
4, and thereafter on Day 2 of every third cycle (i.e. Cycle 7 Day 2, Cycle 10
Day 2, etc.). The starting dose RO7009789 administration will be 1 mg.
In the event that the SC MTD is determined by injection site reactions, the IV
route of administration may be evaluated to establish if greater efficacy or
safety can be achieved. The starting IV dose will be at most 50% of the SC MTD
and not greater than 8 mg. At the MTD for both SC and IV, each cohort will be
expanded to generate PD, PK and safety data to establish the most effective
dose and route of administration for Part II.
In Part II, RO7009789 will be administered at RP2D defined in Part I Q4W on
Cycle 1 Day 2 and then on Cycle 2 Day 2, on Cycle 3 Day 2 and on Cycle 4 Day 2.
Thereafter RO7009789 will be given on Day 2 of every third cycle.
In Part I vanucizumab will be administered intravenously at the fixed dose of 2
g Q2W on Cycle 1 Day1.
In Part II (expansion) vanucizumab will be administered subcutaneously at the
fixed dose of 2 g Q2W on Cycle 1 Day1. The dose of vanucizumab in Part II of
this study may be adapted based on vanucizumab-related safety events or
vanucizumab PK data emerging in Part I.
Treatment with RO7009789 and vanucizumab in Part I and RO7009789 and
bevacizumab in Part II will be continued * potentially beyond radiographic
disease progression * as long as the patient experiences clinical benefit in
the opinion of the investigator. Treatment with RO7009789 and
vanucizmuab/bevacizumab will be discontinued if the patient develops
unacceptable toxicity or withdraws consent.
Study burden and risks
Infusion/Injection-related Reaction (IRR), Immune-mediated Side Events, High
blood pressure, Lack of energy, Constipation, Diarrhea, Abdominal pain,
Vomiting, Nausea, Headache, Swelling of tissues, Cough, Fatigue, Pain in joint,
Shortness of breath, Systemic Immune Activation (SIA), abnormal blood tests,
procedural risks such as tumor biopsies and blood collection.
Severe side effects reported under treatment with vanucizumab include:
Gastrointestinal perforation (damage to any part of the wall of the stomach,
small intestine or large bowel)
Fistula (an abnormal connection between two hollow organs such as blood
vessels, intestines, or other hollow organs)
Bleeding
High blood pressure
Congestive heart failure (damage to the left heart chamber that pumps blood to
the body and can cause fluid in the lungs, which makes breathing difficult)
Thrombotic microangiopathy (a rare disease that results in formation of blood
clots in the smallest blood vessels causing a reduction of blood platelets and
red blood cells and kidney failure)
RO7009789 in combination with vanucizumab could:
Cause venous and arterial blood clots. Blood exams will be closely monitored
during the study and symptoms like breath shortness or leg pain or swelling
will be carefully investigated.
Increase the body*s immune system which may give rise to autoimmune disorders.
Therefore you will be closely monitored for autoimmune reactions (e.g., skin,
digestive system, breathing, underactive thyroid, and liver disease).
Most of the patients who received RO7009789 subcutaneously developed injection
site reactions such as redness, itching, swelling, induration, and tenderness 2
- 9 days later at the site of the injection.
Side effects related to Bevacizumab include:
* Bleeding from the rectum (rectal haemorrhage)
* Diarrhoea
* Nausea and vomiting
* Constipation
* Mucosal inflammation or inflammation of the mouth (stomatitis)
* Loss of appetite (anorexia)
* Abdominal pain
* Weight loss
* Low numbers of white blood cells (neutropenia, leukopenia) and potentially
associated with fever (febrile neutropenia)
* Low numbers of platelets (thrombocytopenia)
* Dry skin, flaking and inflammation of the skin (exfoliative dermatitis)
* Change in skin colour (skin discoloration)
* Numbness or loss of feeling in the fingers or toes (peripheral sensory
neuropathy)
* Change in the sense of taste (dysgeusia)
* High blood pressure (hypertension)
* Shortness of breath (dyspnoea)
* Pain, including headache and joint pain (arthralgia)
* Alteration in speech (dysarthria)
* Protein in urine
* Mucocutaneous bleeding, including nose bleed (epistaxis)
* Lack of energy, weakness (asthenia, fatigue)
* Fever (pyrexia)
* Runny nose (rhinitis)
* Eye disorder, watery eyes (lacrimation increased)
* Fertility problems in women (ovarian failure)
* Nail-related changes
* Delay in wound healing or failure of a wound to heal or spontaneous opening
of a wound
Please refer to section 1.4 BENEFIT RISK ASSESSMENT in the protocol for the
Benefit/Risk rationale.
Beneluxlaan 2a
Woerden 3446 GR
NL
Beneluxlaan 2a
Woerden 3446 GR
NL
Listed location countries
Age
Inclusion criteria
* Part I: Advanced/metastatic histologically confirmed solid tumor (except prostate cancer and squamous NSCLC) not amenable to standard therapy
* Part II: Histologically confirmed diagnosis of advanced/metastatic aPROC, HNSCC and non-squamous NSCLC previously treated with anti-PD-L1 inhibitor alone or in combination
* Age * 18 years
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
* Life expectancy * 16 weeks
* Adequate hematologic and organ function
* Adequate cardiovascular function
* Measurable disease Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
Exclusion criteria
* Patients with prostate cancer or squamous NSCLC
* Patients who have received prior systemic anti-cancer treatment within the following time frames (see protocol for details)
* Treatment with compounds targeting VEGF or VEGF-R within 12 months prior to enrolment (Part II only)
* Treatment with systemic immunosuppressive medications within 2 weeks prior to Cycle 1 Day 1
* Chronic daily treatment with non-steroidal anti-inflammatory drugs (NSAIDs).
However, occasional use for the symptomatic relief of medical conditions (e.g.
headache) is allowed
* Patients who have undergone major surgery within 4 weeks prior to study drug administration
* Patients who have undurgone any abdominal surgery or interventions (including colonoscopy)or
significant abdominal traumatic injury within 60 days prior to Day 1 of
Cycle 1
* Known clinically significant liver disease (with the exception of Gilbert's syndrome)
* History of peripheral venous thrombosis or thromboembolic event (within 12 months prior to Cycle 1 Day 1)
* History of hemoptysis (bronchopulmonary hemorrhage) NCI CTCAE * Grade 2 within 4 weeks prior to study drug administration;
* Metastatic disease that involves major airways or blood vessels, or centrally
located mediastinal tumor masses (< 30 mm from the carina) of large volume
* Significant cardio- or cerebrovascular disease within 6 months prior to Cycle 1 Day 1
* History of intra-abdominal inflammatory process within 6 months prior to
Day 1 Cycle 1, including but not limited to: diverticulitis, peptic ulcer disease,
colitis
* History of bowel obstruction and/or clinical signs or symptoms of
gastrointestinal obstruction including sub-occlusive disease, related to the
underlying disease or a requirement for routine parenteral hydration, parenteral
nutrition, or tube feeding. Patients with signs/symptoms of sub-/occlusive
syndrome/bowel obstruction at time of initial diagnosis may be enrolled if
they had received definitive (surgical) treatment for symptom resolution.
* Evidence of abdominal free air not explained by paracentesis or recent
surgical procedure
* Patients with colonic prosthesis (stent) implant in place (as applicable)
* Severe non-healing wound, active ulcer or untreated bone fracture
* Known primary CNS malignancy or symptomatic or untreated CNS metastases.
* Pregnancy, lactation, or breastfeeding
* History of autoimmune diseases
* Patient with HIV infection, active hepatitis B (chronic or acute), or hepatitis C infection
* Severe infections within 4 weeks prior to Cycle 1 Day 1
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | clinicaltrials.gov |
| EudraCT | EUCTR2015-003480-11-NL |
| CCMO | NL55345.031.15 |