A Randomized, Open-Label Phase 1b/2 Study Evaluating Ramucirumab in Pediatric Patients and Young Adults with Relapsed, Recurrent, or Refractory Desmoplastic Small Round Cell Tumor.

Desmoplastic Small Round Cell Tumor (DSRCT) is a rare tumor that is primarily
found in adolescents and young adults typically involving the abdominal and
pelvic peritoneum. DSRCT, originally described as a mesenchymal entity, is
diagnosed based on the histological and immunohistochemically features of the
tumor and contains the molecular hallmark of the EWS-WT1 fusion protein that
results from the t(11;22)(p13;q12) translocation (Gerald and Rosai 1989; Iyer
et al. 2013). Patients diagnosed with DSRCT have a median survival ranging from
17 to 25 months and long-term survival is uncommon (Dufresne et al. 2012).
Irrespective of the stage of disease, age, and treatment received, the
prognosis of patients with DSRCT is poor, with a 5-year survival of <20%, and
an overall median survival time of 2.1 years (Lal et al. 2005; Honoré et al.
2015; Bent et al. 2016). For patients of all ages, aggressive surgical
debulking (removal of at least 90% of the tumor burden) is the mainstay of the
treatment strategy. The most commonly used treatment plans include
multimodality treatment (radiation, chemotherapy, and surgery). Desmoplastic
small round cell tumor has been shown to be chemosensitive and regimens
designed for treatment of Ewing*s disease are most often followed for initial
treatment. However, no defined standard treatment regimens exist for the
treatment of either upfront or relapsed DSRCT.

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 overall survival, in multiple indications as both a
monotherapy and in 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, double-blind, and
placebo-controlled Phase 3 studies, REGARD (Fuchs et al. 2014) and RAINBOW
(Wilke et al. 2014).

The primary objective of the study is to evaluate the progression free survival
of patients when these are treated with ramucirumab and cyclophosphamide and
vinorelbine, in comparison to treatment without ramucirumab.

The secondary objectives of the study are:
- To evaluate the safety and tolerability of ramucirumab in combination with
cyclophosphamide and vinorelbine compared with cyclophosphamide and vinorelbine
in pediatric and young adult patients with DSRCT.
- To evaluate the efficacy of ramucirumab in combination with cyclophosphamide
and vinorelbine compared with cyclophosphamide and vinorelbine in pediatric and
young adult patients with DSRCT
- To characterize the PK of ramucirumab when co-administered with
cyclophosphamide and vinorelbine in pediatric and young adult patients with
DSRCT
- To assess the immunogenicity of ramucirumab when co-administered with
cyclophosphamide and vinorelbine in pediatric and young adult patients with
DSRCT

Study JV01, 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
DSRCT evaluating ramucirumab in combination with low-dose cyclophosphamide and
vinorelbine. 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 in Study JV02.

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 Statistical Analysis Plan (SAP).

The following treatments will be administered in this study every 4-week
(28-day) cycle.

Ramucirumab is administered intravenously in a 12mg/kg dose and is a one hour
infusion on day 1 and day 15 of the cycle in study arm one.
Cyclophosphamide is administered by oral dose 25mg/m2 in treatment arms 1 and 2
and has to be taken daily
Vinorelbine is administered intravenously (25mg/m2) in study arms 1 and 2 on
day 1, 8 and 15 of each cycle.

As of 31 December 2021, ramucirumab or placebo has been administered either as
a single agent (monotherapy) or in combination with various anti-tumor agents
intravenously to approximately 10669 patients with different cancers in Phase
1/1b, Phase 2, and Phase 3 clinical trials in the ramucirumab development
program. Ramucirumab has been administered subcutaneously to 3 patients in a
Phase 1 study in advanced solid tumors. A single dose of ramucirumab or placebo
has also been administered subcutaneously or intravenously to approximately 50
healthy participants. An estimated 6568 patients have received ramucirumab:
1502 patients received single-agent ramucirumab and 5066 patients received
ramucirumab in combination with other anti-cancer agents.

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 (one kind of white blood cell) count
• Blocking of the arteries by a blood clot
• Blockage of bowel
• Nosebleed
• Rash
• Protein in the urine
• 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.

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 (1a kind of white blood cell) count.

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.

Thyroid dysfunction

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

Heart Failure
Ramucirumab in combination with chemotherapy or erlotinib can cause a condition
when the heart muscle does not pump blood as well as it should, causing
shortness of breath and swelling of the legs and feet.


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 and efficacy 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.