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All Drugs and Chemicals

Antineoplastic Agents

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Antibodies

Pembrolizumab

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Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Cola

1-cycle KFA115 run-in followed by addition of pembrolizumab

KFA115 + pembrolizumab combination given concurrently

KFA115

pembrolizumab

Novartis Pharmaceuticals

Justin Gainor

Amy Ciriaco

Kristen Spencer

Aric Fellers

Jason Luke

Katie Robbins

Melissa Johnson

The purpose of this study is to characterize the safety and tolerability of KFA115 and KFA115 in combination with pembrolizumab in patients with select advanced cancers, and to identify the maximum tolerated dose and/or recommended dose.

This is a phase I, open-label, multi-center study of KFA115 as a single agent and in combination with pembrolizumab. The study consists of a dose escalation part, followed by dose expansion part(s) for single-agent KFA115 and KFA115 in combination with pembrolizumab. The escalation parts will characterize safety and tolerability. After the determination of the maximum tolerated dose (MTD) / recommended dose (RD), the dose expansion parts will assess the preliminary anti-tumor activity in defined patient populations and further assess the safety and tolerability at MTD/RD.

A Study of Safety and Efficacy of KFA115 Alone and in Combination With Pembrolizumab in Patients With Select Advanced Cancers

A Phase I, Open-label, Multi-center Study of KFA115 as a Single Agent and in Combination With Pembrolizumab in Patients With Select Advanced Cancers

A DLT is defined as an adverse event or abnormal laboratory value that occurs during the DLT evaluation period where the relationship to study treatment cannot be ruled out, and is not primarily related to disease, disease progression, intercurrent illness, or concomitant medications and meets the criteria defined in the study protocol

Incidence and severity of adverse events and serious adverse events, including changes in laboratory values, vital signs, and electrocardiograms qualifying and reported as AEs

Number of dose interruptions of KFA115 and pembrolizumab, and number of dose reductions of KFA115

Dose intensity of KFA115 and pembrolizumab is defined as the ratio of actual cumulative dose received and actual duration of exposure

BOR is defined as the best response recorded from the start of the treatment until disease progression/recurrence

PFS is defined as the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause

DOR is defined as the time from the date of the first documented response (CR or PR) to the date of the first documented progression as per RECIST v1.1 or death due to underlying cancer

TTP is defined as the time from date of start of treatment to the date of event defined as the first documented progression or death due to underlying cancer

The maximum (peak) observed plasma or serum drug concentration after single dose administration

The minimum observed plasma or serum drug concentration reached during the time interval between two dose administrations

The time to reach maximum (peak) plasma or serum drug concentration after single dose administration

The elimination half-life associated with the terminal slope of a semi logarithmic concentration-time curve

Pharmaceutical Solutions

Trametinib

Dabrafenib

Spartalizumab

Protein Kinase Inhibitors

Enzyme Inhibitors

In Part 1, participants are treated at different dose levels to determine the recommended Phase 3 regimen of spartalizumab in combination with dabrafenib and trametinib. The starting dose of spartalizumab is 400 mg Q4W in combination with the approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD).

In Part 2, participants are treated with spartalizumab 400 mg Q4W in combination with the approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD).

In Part 3, participants are randomized to receive spartalizumab at the RP3R identified in Part 1 (400 mg Q4W) in combination with approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD)

In Part 3, participants are randomized to receive matching placebo in combination with the approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD)

Spartalizumab powder for solution is used in Part 1 and Part 2, and as concentrate for solution for infusion for Part 3. Spartalizumab is administered via intravenous infusion over 30 minutes once every 4 weeks

Placebo is administered via intravenous infusion over 30 minutes once every 4 weeks

Placebo

Dabrafenib 150 mg capsules BID is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions.

Trametinib 2 mg tablets QD is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions

To evaluate the safety and efficacy of the combination of an anti-PD-1 antibody (Spartalizumab (PDR001)), a BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib) in unresectable or metastatic BRAF V600 mutant melanoma

This study is designed as a Phase III, multi-center study consisting of three parts:

* Part 1, known as the Safety Run-in, is an open-label part aimed at determining the recommended Phase III regimen (RP3R) of spartalizumab in combination with dabrafenib and trametinib for previously untreated subjects with BRAF V600 mutant unresectable or metastatic melanoma (Stage IIIC/IV per AJCC edition 7). In Part 1, spartalizumab was administered at a starting dose level (DL1) of 400 mg every 4 weeks (Q4W), along with fixed doses of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily). The RP3R for Part 3 was determined using the Bayesian Logistic Regression Model (BLRM) with escalation with overdose control (EWOC) criteria.
* Part 2, referred to as the Biomarker Cohort, is an open-label section focused on characterizing the kinetics of immune biomarkers and potential immune resistance mechanisms. Part 2 started when the fourth subject in dose level 1 (DL1) of Part 1 completed approximately 4 weeks of study treatment, and fewer than 3 dose-limiting toxicities (DLTs) were observed. Participants in Part 2 receive PDR001 (spartalizumab) at a dosage of 400 mg Q4W, in combination with dabrafenib (150 mg BID) and trametinib (2 mg QD).
* Part 3 is a double-blind, randomized, placebo-controlled phase that compares the efficacy and safety of spartalizumab in combination with dabrafenib and trametinib to placebo in combination with dabrafenib and trametinib. Part 3 was initiated after determining the RP3R for the combination of spartalizumab with dabrafenib and trametinib in Part 1. Subjects were randomized in a 1:1 ratio to receive either the RP3R dose of spartalizumab identified in Part 1 or placebo, along with dabrafenib (150 mg BID) and trametinib (2 mg QD).

For all parts of the study, the treatment is continued until the subject experiences any of the following events: disease progression according to RECIST 1.1 as determined by the Investigator, unacceptable toxicity, initiation of a new anti-neoplastic therapy, pregnancy, withdrawal of consent, physician's decision, loss to follow-up, death, or termination of the study by the Sponsor. Safety evaluations are conducted for all subjects for up to 150 days after the last dose of spartalizumab/placebo (safety follow-up period).

Subjects who discontinue study treatment without disease progression as per RECIST 1.1 continue with tumor assessments according to the protocol until documented disease progression, withdrawal of consent, loss to follow-up, or death, regardless of the initiation of new anti-neoplastic therapy (efficacy follow-up period).

Subjects enter the survival follow-up period after completing the safety follow-up period or experiencing disease progression as per RECIST 1.1 or response criteria for immunotherapy, whichever period is longer (survival follow-up period).

Part 1 and Part 2 are open- label. Part 3 is double-blind and randomized.

A Study of the Anti-PD1 Antibody PDR001, in Combination With Dabrafenib and Trametinib in Advanced Melanoma

A Randomized, Double-blind, Placebo-controlled, Phase III Study Comparing the Combination of PDR001, Dabrafenib and Trametinib Versus Placebo, Dabrafenib and Trametinib in Previously Untreated Patients With Unresectable or Metastatic BRAF V600 Mutant Melanoma

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

DLT was defined as an adverse event or abnormal laboratory value that was unrelated to disease, disease progression, inter-current illness, or concomitant medications and occured within 8 weeks of treatment with spartalizumab in combination with dabrafenib and trametinib. The DLT criteria included Grade 4 hematological adverse events, Grade 4 bilirubin elevation, specific gastrointestinal adverse events, symptomatic serum amylase or lipase elevation, Grade 3 or higher hypertension, Grade 3 or higher cardiac events, Grade 2 or higher pneumonitis, Grade 3 or higher immune-related toxicities, infusion-related reactions, other clinically significant adverse events, and toxicities leading to a dosing delay of over 12 weeks. NCI CTCAE v4.03 was used for grading DLTs

Change from baseline in PD-L1 expression (as determined by immunohistochemistry in tissue samples) upon treatment with spartalizumab in combination with dabrafenib and trametinib in participants from Part 2

Change from baseline in CD8+ cells (as determined by flow cytometry in blood samples) upon treatment with spartalizumab in combination with dabrafenib and trametinib in participants from Part 2

Progression-free survival was defined as the time from the date of first dose to the date of the first documented radiological progression per investigator's assessment according to RECIST 1.1 or death due to any cause. The distribution of PFS was estimated using the Kaplan-Meier (KM) method. If a patient had not had an event at the time of data cut-off, progression-free survival was censored at the date of last adequate tumor assessment.

Overall survival is defined as the time from date of randomization to date of death due to any cause

ORR was defined as the percentage of subjects with confirmed best overall response of complete response (CR) or partial response (PR), as per investigator's assessment by RECIST 1.1.

CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \<10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters

DOR was defined as the time from first documented response of CR or PR to date of first documented progression or death, according to RECIST 1.1 criteria. The distribution of DOR was estimated using the KM method.

CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \<10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters

DCR was defined as the percentage of participants with CR or PR or subjects with stable disease (SD) lasting for a duration of at least 24 weeks as per local review according to RECIST 1.1 criteria.

CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \<10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.

The EORTC QLQ-C30 was a 30-item questionnaire that patients complete, consisting of both multi-item scales and single-item measures. It included five functional scales, three symptom scales, six single items, and a Global Health Status/Quality of Life (GHS/QoL) scale.

The GHS/QoL scale had seven possible response scores ranging from 1 (very poor) to 7 (excellent), which were averaged and transformed to a 0-100 scale. A higher score on this scale indicated a better quality of life.

The change from baseline in GHS/QoL scores was calculated. A positive change from baseline indicated improvement in the patient's quality of life.

The EORTC QLQ-C30 was a patient completed 30 item questionnaire that was composed of both multi-item scales and single-item measures. These included five functional scales, three symptom scales, six single items and a global health status/QoL scale.

The EORTC QLQ-C30 physical functioning scale measured a patient's ability to carry out daily activities and tasks requiring physical exertion. It consisted of five questions asking patients to rate their level of physical functioning, with response options ranging from 1="not at all" to 4="very much". The scores for each item were summed and transformed to a 0 to 100 scale, with higher scores indicating better physical functioning.

The change from baseline in physical functioning scale scores was calculated. A positive change from baseline indicated improvement in physical functioning.

The EORTC QLQ-C30 was a patient completed 30 item questionnaire that was composed of both multi-item scales and single-item measures. These included five functional scales, three symptom scales, six single items and a global health status/QoL scale.

The EORTC QLQ-C30 pain symptom scale was one of the symptom scales in the questionnaire, which measured the severity of pain experienced by the patient. The pain symptom scale consisted of two items, one measuring the severity of pain and the other measuring the use of painkillers. The items were rated on a 4-point scale ranging from 1="not at all" to 4="very much". The scores for each item were summed and transformed to a 0 to 100 scale, with higher scores indicating more severe pain.

The change from baseline in pain symptom scale scores was calculated. A negative change from baseline indicated improvement.

The EORTC QLQ-C30 was a patient completed 30 item questionnaire that was composed of both multi-item scales and single-item measures. These included five functional scales, three symptom scales, six single items and a global health status/QoL scale.

The GHS/QoL scale had seven possible response scores ranging from 1 (very poor) to 7 (excellent), which were averaged and transformed to a 0-100 scale. A higher score on this scale indicated a better quality of life.

The time to definitive 10 point deterioration is defined as the time from the date of randomization to the date of event, which is defined as at least 10 points relative to baseline worsening of the GHS/QoL score or death due to any cause. If a subject had not had an event, the time to deterioration was censored at the date of the last adequate assessment. The distribution was estimated using KM method.

The Functional Assessment of Cancer Therapy-Melanoma (FACT-M) quality of life questionnaire was composed of the FACT-General (FACT-G) plus the Melanoma Subscale and the Melanoma Surgery Subscale, which complemented the general scale with items specific to quality of life (QoL) in melanoma.

The Melanoma Subscale of FACT-M included 16 questions, with response options of 0= "Not at all", 1= "a little bit", 2= "somewhat", 3= "quite a bit" and 4= "very much". The FACT-M melanoma subscale score ranged from 0 to 64, with higher scores indicating a higher quality of life in relation to melanoma.

The change from baseline in melanoma subscale scores was calculated. A positive change from baseline indicated improvement.

The EQ-5D-5L is a standardized questionnaire used to assess health-related quality of life, and it includes a Visual Analog Scale (VAS). The VAS score is obtained by asking the individual to rate their current health status on a scale from 0 to 100, where 0 represents the worst possible health state and 100 represents the best possible health state.

The change from baseline in EQ-5D-5L VAS score was calculated. A positive change from baseline indicates improvement in the health status.

PFS was defined as the time from the date of first dose to the date of the first documented radiological progression as per investigator's assessment using RECIST 1.1 response criteria or death due to any cause. The distribution of PFS was estimated using the KM method. If a patient had not had an event at the time of data cut-off, progression-free survival was censored at the date of last adequate tumor assessment.

PFS analysis was performed by PD-L1 status (positive, negative) where a positive status was defined as having ≥ 1% expression and a negative status was defined as having \< 1% expression.

OS is defined as the time from date of randomization to date of death due to any cause.

OS analysis will be performed by PD-L1 subgroup (positive, negative) where a positive status is defined as having ≥ 1% expression and a negative status is defined as having \< 1% expression.

Spartalizumab ADA prevalence at baseline was calculated as the percentage of participants who had an spartalizumab ADA positive result at baseline.

Spartalizumab ADA incidence was calculated as the percentage of participants who were treatment-induced spartalizumab ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted spartalizumab ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer)

Ctrough for spartalizumab refers to the serum concentration of spartalizumab immediately prior to the administration of a dose of spartalizumab on Day 1 of Cycle 2 and later cycles.

Plasma concentration of dabrafenib immediately prior to the administration of a dose of dabrafenib.

Plasma concentration of trametinib immediately prior to the administration of a dose of trametinib.

Number of participants with dose interruptions for spartalizumab, dabrafenib and trametinib

Number of patients with dose reductions for spartalizumab, dabrafenib and trametinib

Relative dose intensity for spartalizumab, dabrafenib and trametinib computed as the ratio of dose intensity and planned dose intensity

Treatment-emergent Adverse Events: Any sign or symptom that occured during the study treatment plus 30 days post treatment in the Safety Set (treated patients only). All-Cause Mortality is using the Full Analysis Set, including all participants to whom study treatment was assigned by randomization (Part 3) and all participants to whom study treatment was assigned and who received at least one one of any study treatment (Part 1 and 2)

Deaths were collected in the pre-treatment period (from day of patient's informed consent to the day before first administration of study treatment )

All Participants (Pre-treatment)

AEs during on-treatment period and post-treatment safety follow-up (up to 150 days post-treatment)

Part 1: Safety run-in Cohort (On-treatment and Post-treatment Safety FU)

Deaths collected in the post-treatment survival follow-up period (starting from day 151 post- treatment). No AEs were collected during this period

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of Safety and Efficacy of KFA115 Alone and in Combination With Pembrolizumab in Patients With Select Advanced Cancers	NCT05544929	Carcinoma, Non-... Cutaneous Melan... Carcinoma, Rena... Carcinoma, Ovar... Nasopharyngeal ... Carcinoma, Thym... Anal Cancer Mesothelioma Esophagogastric... High Microsatel... Squamous Cell C... Triple Negative...	KFA115 pembrolizumab	18 Years -	Novartis
A Study of the Anti-PD1 Antibody PDR001, in Combination With Dabrafenib and Trametinib in Advanced Melanoma	NCT02967692	Melanoma	Spartalizumab Placebo Dabrafenib Trametinib	18 Years -	Novartis
Study to Investigate the Objective Response Rate of Dabrafenib in Combination With Trametinib in Subjects With BRAF V600 Mutation-Positive Melanoma	NCT02083354	Cancer Melanoma	Dabrafenib Trametinib	18 Years -	Novartis
A Study of Safety and Efficacy of KFA115 Alone and in Combination With Pembrolizumab in Patients With Select Advanced Cancers	NCT05544929	Carcinoma, Non-... Cutaneous Melan... Carcinoma, Rena... Carcinoma, Ovar... Nasopharyngeal ... Carcinoma, Thym... Anal Cancer Mesothelioma Esophagogastric... High Microsatel... Squamous Cell C... Triple Negative...	KFA115 pembrolizumab	18 Years -	Novartis
A Study of the Anti-PD1 Antibody PDR001, in Combination With Dabrafenib and Trametinib in Advanced Melanoma	NCT02967692	Melanoma	Spartalizumab Placebo Dabrafenib Trametinib	18 Years -	Novartis

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