KEYNOTE D58

Tumor Treating Fields (TTFields) are electric fields that exert physical forces capable of disrupting cellular processes critical for cancer cell viability and tumor progression. In pre-clinical data, TTFields were shown to be able to inhibit tumor growth and even induce tumor cells death through multiple mechanisms. When it comes to cancer cells specifically, TTFields can interfere with their division (slow down or even stop it), impair their DNA damage repair, and even alter the ability to migrate to different regions of the body. Systemically, laboratory experiments suggest TTFields have the ability to contribute to an anti-tumor response through enhancing the body’s immune system reaction to the tumor.

TTFields are delivered to the body region where the primary tumor is located using a medical device called Optune^®. Optune is a portable, battery-operated device designed to deliver TTFields of 200kHz.

Patients receiving TTFields need to wear four adhesive patches called transducer arrays (arrays) on their scalp, which deliver the fields non-invasively to the location of the GBM tumor. The device is intended for continuous home use by patients.

Optune^® delivers TTFields to the brain and has been approved by the FDA under the Premarket Approval (PMA) pathway for the treatment of adults with recurrent and newly diagnosed glioblastoma. Optune has a CE Mark in Europe for the treatment of glioblastoma and is also approved in Japan and Greater China. This study will assess if Optune can help patients when used concomitantly with TMZ and Pembrolizumab.

The KEYNOTE D58 study (also known as EF-41) is a phase 3, randomized, double-blind, placebo-controlled study of Optune^® (TTFields, 200 kHz) concomitant with maintenance temozolomide and pembrolizumab versus Optune^® concomitant with maintenance temozolomide and placebo for the treatment of newly diagnosed glioblastoma.

The study is expected to enroll 741 patients across the globe.

This study is intended for newly diagnosed GBM patients who had debulking surgery/biopsy only and were treated with radiation therapy (RT) concomitant with temozolomide (TMZ).

Final eligibility can only be determined by a study physician at one of the clinical study sites.

Once the study physician has determined that all requirements for participation in the study are met, patients will be randomly assigned to one of two groups:

• The Treatment Group: Optune^® + TMZ + pembrolizumab, which is an immunotherapy drug
• The Control Group: Optune^® + TMZ + placebo, which is an inactive substance that looks the same as and is given the same way as pembrolizumab

The patients will have a double chance of being assigned to the treatment group. As this is a double-blind study, the patients, the study physician, and the Novocure study team will not know to which of the groups the patients have been assigned until the end of the study.

Patients who are randomly assigned to the treatment group will receive pembrolizumab, which will be given intravenously (injection in the vein) at the hospital or outpatient clinic. For patients who are randomly assigned to the control group, a placebo, i.e. saline solution, will be administered the same way as pembrolizumab.

Patients will receive pembrolizumab or placebo until first disease progression or up to 35 cycles (approximately 2 years). TMZ will be administered for at least 6 cycles. TTFields treatment will continue until second disease progression or 24 months (the earlier of the two). Patients may continue to receive TTFields treatment beyond second disease progression or 24 months until loss of clinical benefit at the discretion of the study physician. In case any where the treatment discontinuation conditions are met, treatment will be stopped.

By participating in the study, all participants are assisting researchers in providing additional information and data used to assess the efficacy of TTFields, with the goal to assist future patients with this disease.

To receive TTFields treatment, the patient needs to wear four adhesive patches called transducer arrays (or arrays), applied directly to their scalp. Transducer array placement requires the shaving of the entire scalp before starting to use the device, and at least twice a week as long as the patient continues to use TTFields.

The use of the device will include training on the operation of the equipment by a qualified Device Support Specialist (DSS) or a designated health care provider from the study site.

Once trained, patients can setup and use the device themselves (with the help of a family member or a caregiver if needed) or may receive support from a designated health care provider from the study site or a DSS.

The device is designed to be user-friendly, and all technical aspects related to using it are maintained by the DSS. The DSS can also help patients in finding technical solutions to allow each individual to receive TTFields while maintaining his/her normal daily routines.

This is just a summary of eligibility criteria. To see the complete list of eligibility criteria please go to clinicaltrials.gov or consult with a KEYNOTE D58 study physician.

Key Inclusion Criteria

1. The participant (or legally acceptable representative) has provided documented informed consent for the study.
2. Be ≥ 18 years of age on the day of providing informed consent.
3. Participant with new diagnosis of GBM according to WHO 2021 Classification.
4. Recovered from maximal debulking surgery (gross total resection, partial resection and biopsy-only patients are all acceptable), Gliadel wafers placement at the time of surgical resection is allowed.
5. Have completed standard adjuvant chemoradiotherapy of RT according to local practice (56-64 Gy), and concomitant TMZ chemotherapy.
6. Able to start treatment at least 4 weeks from the latter of the last dose of concomitant temozolomide or radiotherapy.
7. Amenable to treatment with Optune concomitant with maintenance temozolomide (150-200 mg/m^2 daily x 5, Q28 days).
8. All patients must have had tissue submitted for MGMT Promoter Methylation determination prior to randomization.
9. Have an ECOG Performance Status of 0 to 1 assessed within 7 days before randomization.
10. Life expectancy ≥ 3 months.

Key Exclusion Criteria

1. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137).
2. Ongoing requirement for >2 mg dexamethasone (or equivalent), due to intracranial mass effect.
3. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to randomization.
4. Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed.
5. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first study treatment.
6. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication.
7. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.

The study is expected to enroll 741 patients across the globe. Please contact one of the participating centers if you would like to participate in or learn more about the study.

Patients participating in the KEYNOTE D58 study will use the device continuously for at least 18 hours a day (monthly average), but may take breaks during daily use for some activities. The study physician may modify the treatment schedule and use of the device as needed.

The Device Support Specialist (DSS) or a designated health care provider from the study site will provide device support to patients and their caregivers.

Please note: While the DSS may provide comprehensive device and technical support, they do not offer medical advice. Please direct all medical questions to your study physician.

Optune is intended for continuous use for at least 18 hours a day (monthly average). The device does not interfere with household or personal electrical devices. There is no exposure of TTFields to non-users, such as co-workers and family members.

Optune is a wearable, portable device. Use of the device requires shaving of the contact site and the application of arrays to the scalp. Naturally, some patients may be concerned about their appearance or their lifestyle while using the device. The arrays and the wires connecting to the device may be concealed underneath the patient’s clothes and or a head covering or hat. By doing so, the bag carrying the device may be the only element of the device visible to others. The medical team at the study site and DSS will provide personalized assistance specific to each patient on how best to wear the device.

In addition to shaving the head regularly, patients will change their arrays to ensure continuous treatment. The medical team at the study site will assist in creating a plan and instructing patients and their caregivers on array placement.

The device is designed to give patients the option to maintain their lifestyle without interference to their daily routines. Patients can consult their study physician ahead of time regarding any activity in question. In addition, the DSS can provide information to address any lifestyle concerns.

The device bags can be worn as a shoulder bag, a backpack, a messenger bag, a hip bag or hand-held. The total weight of the device including a battery is around 1.3 kilograms, or 2.7 pounds. The device is powered by rechargeable batteries, and patients will receive several to ensure continuous use is feasible. If needed, Novocure can provide additional portable batteries.

In order to ensure continuous treatment, patients can plug the device in to an AC adapter when staying in a location for more than a few hours.

Cancer cells divide and multiply rapidly within the tumor location. These cancer cells carry different types of electrically charged elements that play a role during the cell division process. Other healthy cells in the brain multiply at a much slower rate, if at all.

The Optune device delivers low-intensity, wave-like electric fields to the location of the tumor. These fields are known as Tumor Treating Fields (TTFields).

Preclinical studies showed that due to the shape and size of cancer cells when they are multiplying, TTFields cause electrically-charged cellular components of these cells to change their location within the dividing cell, disrupting their normal function and may ultimately lead to cell death.

In addition, cancer cells also contain miniature building blocks that act as tiny motors in moving essential parts of the cells from place-to-place. TTFields interfere with the normal orientation of these tiny motors since they are also electrically charged. As a result, the cancer cell division is slowed, or even stopped, inhibiting tumor growth.

A summary of TTFields’ mechanism of action is illustrated in the following animation:

A number of systems developed to deliver TTFields to different tumor types have been tested to date. The frequency is adjusted by the manufacturer in order to optimize the treatment for specific tumor types, based on data from laboratory experiments.

Optune^® delivers TTFields to the brain and has been approved by the FDA under the Premarket Approval (PMA) pathway for the treatment of adults with recurrent and newly diagnosed glioblastoma. Optune has a CE Mark in Europe for the treatment of glioblastoma and is also approved in Japan and Greater China. This study will assess if Optune can help patients when used concomitantly with TMZ and Pembrolizumab.

TTFields

Based on the science behind TTFields and the clinical results to date, Optune is not expected to have systemic side effects in patients with newly diagnosed glioblastoma. In previous studies performed with Optune, a high percentage of patients have experienced local skin irritation beneath the transducer arrays, which was mild to moderate in severity in the vast majority of cases. The information provided in this website is partial, and you should consult with your study physician concerning the complete safety profile of TTFields.

Pembrolizumab

Pembrolizumab can cause your immune system to attack normal organs and tissues in your body and can affect the way they work, which can result in side effects. These side effects can affect more than one of your normal organs and tissues at the same time.

The objective of this study is to evaluate the safety and efficacy of Tumor Treating Fields (TTFields, 200 kHz) delivered by the Optune^® device concomitant with maintenance temozolomide and pembrolizumab compared to Optune^® concomitant with maintenance temozolomide and placebo for the treatment of newly diagnosed glioblastoma.

Please contact an investigator at the study center closest to you.

Patients may not necessarily be physically carrying the device all of the time, but will rather use it while it is continuously placed in one location (e.g. on a desk, a table or on the floor inside the carrying bag). The device was designed to allow the performance of normal daily routines. The device and the portable battery weigh about 1.3 kilograms, or 2.7 pounds, altogether and can be carried in a dedicated shoulder bag or backpack when walking around.

TTFields treatment is not expected to have systemic side effects, based on our clinical data to date. Some patients have experienced skin irritation beneath the arrays. When TTFields are delivered, the arrays may cause mild warming and tingling of the skin underneath them.

Please consult with a study physician at one of the centers participating in the study for additional information about potential side effects from using the device and the other treatments in the clinical study.

There is no exposure of TTFields to non-users, such as co-workers and family members. The use of the device will not interfere with household or standard personal electrical devices.

You can use the device while maintaining most of your daily routines. The arrays may be concealed underneath your clothes. The Device Support Specialist (DSS) will offer help and support related to appearance issues if you are using TTFields.