A Randomized, Open-Label Phase 2 Study Evaluating Ramucirumab in Pediatric Patients and Young Adults with relapsed, Recurrent, or Refractory Synovial Sarcoma.

Synovial Sarcoma is the most common non-rhabdomyosarcoma STS in children and
adolescents and makes up 10% of all STSs (Soole et al. 2014). SS is found in
both pediatrics and adults and is classified as a malignant mesenchymal tumor,
characterized by local invasiveness and a propensity to metastasize (Ferrari et
al. 2015). These tumors arise in close proximity to tendon sheaths, joint
cavities, and bursae and often metastasize to the lungs or lymph nodes
(Stanelle et al. 2013). Treatment strategies have been difficult to identify
due to low incidence and unusual clinical behavior that does not follow typical
patterns of local recurrence, metastasis, or response to treatment. For both
adult and pediatric patients with SS, the current standard approach for local
disease is surgical resection; radiation therapy and/or chemotherapy may be
given before or after surgery. As a chemosensitive malignancy, SS tumors have
shown response to ifosfamide-based chemotherapy (typically in combination with
doxorubicin, and generally with multimodal therapy). However, there is no
defined standard treatment regimen in the relapsed setting.
Despite initial treatment, approximately 25% to 40% of pediatric patients with
SS who initially present with local tumors develop recurrent or refractory
disease; in these patients the 5-year overall survival (OS) is just 30% to 42%
after relapsing (Ferrari et al. 2015; Soole et al. 2014).

Ramucirumab is a human receptor-targeted monoclonal antibody (mAb) that
specifically binds VEGF Receptor 2. The binding of ramucirumab to VEGF Receptor
2 prevents its interaction with activating ligands (VEGF-A, VEGF-C, and
VEGF-D). As a result, ramucirumab inhibits ligand-stimulated activation of VEGF
Receptor 2 and its downstream signaling components, including p44/p42
mitogen-activated protein kinases. This neutralizes ligand-induced
proliferation and migration of human endothelial cells and ultimately inhibits
tumor growth and propagation.

Ramucirumab has not been approved in pediatrics; however, is being studied in
the ongoing I4T-MC-JVDA (JVDA) trial. In adults, ramucirumab has improved
outcomes, including OS, in multiple indications as both a monotherapy and
combination with other agents. Ramucirumab is approved as monotherapy or in
combination with paclitaxel in the United States (US), the European Union (EU),
Japan, and other countries for the treatment of adult patients with advanced
gastric cancer or gastroesophageal junction (GEJ) adenocarcinoma with disease
progression on or after prior platinum and/or fluoropyrimidine chemotherapy.
The approvals were based on the clinical efficacy and safety demonstrated in 2
global, randomized, doubleblind, and placebo-controlled Phase 3 studies, REGARD
(Fuchs et al. 2014) and RAINBOW (Wilke et al. 2014).

Primary:
- To evaluate the progression free survival in patients who are treated with
ramucirumab in combination with gemcitabine and docetaxel compared with
gemcitabine and docetaxel in pediatric and young adult patients with SS.

Secondary:
- To evaluate the safety and tolerability of ramucirumab in combination with
gemcitabine and docetaxel compared with gemcitabine and docetaxel in pediatric
and young adult patients with SS.
- To evaluate the efficacy of ramucirumab in combination with gemcitabine and
docetaxel compared with gemcitabine and docetaxel in pediatric and young adult
patients with SS.
- To characterize the PK of ramucirumab when co-administered with gemcitabine
and docetaxel in pediatric and young adult patients with SS.
- To assess the immunogenicity of ramucirumab when co-administered with
gemcitabine and docetaxel in pediatric and young adult patients with SS.

Exploratory:
- To explore additional measures of the efficacy of ramucirumab in combination
with gemcitabine and docetaxel compared with gemcitabine and docetaxel in
pediatric and young adult patients with SS.
- To explore the associations between biomarkers, disease state, and clinical
outcomes

Study JV02, combined with Protocol J1S-MC-JAAA (hereinafter referred to as the
CAMPFIRE Master Protocol), is a Phase 2, randomized investigation in pediatric
patients and young adults diagnosed with relapsed, recurrent, or refractory SS
not amendable to surgery evaluating
ramucirumab in combination with gemcitabine and docetaxel. Patients will be
randomized at a ratio of 2:1 to receive either experimental or control therapy
respectively.

The primary endpoint of the study (PFS) will be evaluated via a Bayesian
analysis incorporating information regarding historical control outcomes as
well as effect-size observed on Study JV01.

This design allows for a reduced proportion of patients to be randomized to
control therapy while maintaining power in light of sample-size limitations
associated with the underlying rarity of the disease. Details of the Bayesian
analysis are provided in the SAP,

As of 31 December 2020, ramucirumab or ramucirumab/placebo has been
administered either as a single agent (monotherapy) or in combination with
various anti-tumor agents to approximately 10637 patients with different
cancers in Phase 1/1b, Phase 2, and Phase 3 clinical trials in the ramucirumab
development program. An estimated 6501 patients have received ramucirumab: 1452
patients received single-agent ramucirumab and 5049 patients received
ramucirumab in combination with other anti-cancer agents. A single dose of
ramucirumab has also been administered subcutaneously or intravenously to
approximately 28 healthy participants.

This Risk Profile is based on safety data from clinical trials in which
patients were either treated with ramucirumab as a single agent (monotherapy)
or in combination with other anti-cancer agents.

Risks and discomforts associated with ramucirumab are described below by
cancer type in the following categories

- Gastric Cancer
- Single-agent Ramucirumab
Very Common Side Effects (>=10% of study population)
• Stomach pain
• High blood pressure
• Loose stools

Common Side Effects (>=1% to <10% of patients)
• Headache
• Low levels of important chemicals, such as potassium and sodium, in the blood
• Low neutrophil (a kind of white blood cell) count
• Blocking of the arteries by a blood clot
• Blockage of bowel
• Nosebleed
• Rash
• Protein in the urine

Uncommon Side Effects (<1% of patients)
• Tears (perforations) in the walls of the stomach or intestines

-Hepatocellular Carcinoma
-Single Agent Ramucirumab
Very Common Side Effects (>=10% of study population)
• Feeling tired/lack of energy/weakness
• Accumulation of fluid, causing swelling in tissues in body areas such as the
legs
• High blood pressure
• Stomach pain
• Decrease or loss of appetite
• Loss of sleep
• Fever
• Nausea
• Belly swelling due to fluid build-up
• Vomiting
• Protein in the urine
• Headache
• Nosebleed
• Back pain
• Low platelet count,
• Abnormally low level of protein (albumin) in the blood.

Common Side Effects (>=1% to <10% of patients)
• Decreased brain function in patients with liver damage/failure
• Decline in kidney function in patients with liver failure,
• Low neutrophil (a kind of white blood cell) count.
• Reactions related to infusion of ramucirumab: symptoms may include shaking,
back pain or spasms, chest pain and/or tightness, feeling cold,
red skin, trouble breathing, rash, fever, headache, body aches, stomach
pain, nausea, vomiting, blurry vision, alterations in heart rate and
blood pressure, low blood pressure, and tingling or burning in the
hands or feet.

Other Data Associated with Ramucirumab across Trials

Abnormal or slow/poor healing of wounds

Ramucirumab may increase the risk of abnormal or slow/poor healing of wounds.
You should not receive ramucirumab for at least 4 weeks before you undergo
planned surgery and your doctor will decide when to re-start treatment based on
clinical judgment of adequate wound healing. If a patient develops abnormal or
slow/poor healing of wounds during therapy, ramucirumab should be discontinued
until the wound is fully healed.

Risk of liver failure and other significant liver injury

Patients with scarring of the liver with moderate to severe impairment of
liver function are at a higher risk of developing liver failure. Signs of liver
failure include high levels of liver enzymes in the blood, belly swelling due
to fluid build-up, changes in brain function, and decline in kidney function.
These events have the potential to be life-threatening or fatal.

Abnormal tube-like connections or passageways inside the body called fistulas
Ramucirumab may increase the risk of developing abnormal tube-like connections
or passageways inside the body between a hollow or tubular organ and the body
surface, or between two hollow or tubular organs. Ramucirumab treatment should
be discontinued in patients who develop abnormal tube-like connections or
passageways inside the body.
Changes in brain function and structure

Thyroid dysfunction
Ramucirumab may affect the function of thyroid, resulting in decreased
production of certain important hormones.

Adverse reactions from spontaneous reporting
Common side effects
• Abnormal growth of blood vessels, usually on the surface of the skin. This
may appear as a red, raised lesion and may grow larger and/or
bleed (hemangioma).
• Altered voice, such as hoarseness.
• Abnormally low activity of the thyroid gland

Rare side effects
Abnormal blood clotting in small blood vessels in various organs of the body,
most commonly in the kidney, and leading to decreased blood flow and possible
damage to organs (thrombotic microangiopathy). Red blood cells (which carry
oxygen) and platelets (which help the blood to clot) may be destroyed.
Symptoms of thrombotic microangiopathy include bruising/bleeding, tiredness,
shortness of breath, decreased urine output, swollen legs, headache, confusion,
and symptoms of stroke. Protein in the urine and high blood pressure may
occur.

Posterior reversible encephalopathy syndrome (PRES), a rare, but serious, brain
disorder has been reported in patients treated with ramucirumab. Signs and
symptoms of PRES may include headache, seizures, visual changes, and changes in
mental function, with or without high blood pressure. These symptoms usually
stop or improve within days, but some patients can experience continuing
changes in mental function or death. Ramucirumab should be permanently
discontinued in patients who experience PRES.

The use of the drugs in the same class as ramucirumab may increase the risk of
developing an enlargement and weakening of a blood vessel wall (aneurysm), a
tear in a blood vessel wall (dissection), or a rupture of a blood vessel.
Patients with a history of high blood pressure or aneurysm may be at a higher
risk of developing these events.


Risks in Pregnant or Nursing Women and Women of Child Bearing Potential
For women of child bearing potential or women who become pregnant during
treatment with ramucirumab, there may be risks to the unborn child and for
maintaining pregnancy. Ramucirumab may affect the growth of new blood vessels
and may potentially have undesirable effects during pregnancy and development
after birth. Women should consider the use of birth control to avoid getting
pregnant while receiving ramucirumab and for at least 3 months after the last
dose of ramucirumab.
There are no available data on ramucirumab use in pregnant women. Pregnant
women should avoid the use of ramucirumab and only use if the potential benefit
to the mother justifies the potential risk to the unborn child.
Studies have not been conducted to assess ramucirumab*s impact on milk
production, its presence in breast milk, or its effects on the breast-fed
child. If breastfeeding, it is recommended to discontinue nursing or
discontinue ramucirumab.

Risks in Children
Ramucirumab is under evaluation for use in children (aged <12 years) or
adolescents (aged 12 to <18 years). Despite limited clinical data, no new
safety concerns were observed from 1 small completed study in children and
young adult patients. The safety and efficacy have not yet been established in
this group of patients. Based on an animal study with ramucirumab, changes in
the growth plates of bones are a possible risk in children. If changes in the
growth plates of bones occur, future effects on bone growth may be possible.